CN1842320B - Formulations for coated microprojections containing non-volatile counterions - Google Patents

Formulations for coated microprojections containing non-volatile counterions Download PDF

Info

Publication number
CN1842320B
CN1842320B CN2004800243347A CN200480024334A CN1842320B CN 1842320 B CN1842320 B CN 1842320B CN 2004800243347 A CN2004800243347 A CN 2004800243347A CN 200480024334 A CN200480024334 A CN 200480024334A CN 1842320 B CN1842320 B CN 1842320B
Authority
CN
China
Prior art keywords
acid
ph
formulation
non
volatile
Prior art date
Application number
CN2004800243347A
Other languages
Chinese (zh)
Other versions
CN1842320A (en
Inventor
M·阿梅里
林伟琦
M·J·N·科尔米尔
马御方
Original Assignee
阿尔扎公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US48402003P priority Critical
Priority to US60/484,020 priority
Application filed by 阿尔扎公司 filed Critical 阿尔扎公司
Priority to PCT/US2004/021004 priority patent/WO2005004842A2/en
Publication of CN1842320A publication Critical patent/CN1842320A/en
Application granted granted Critical
Publication of CN1842320B publication Critical patent/CN1842320B/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/46Medical treatment of waterborne diseases characterized by the agent
    • Y02A50/468The waterborne disease being caused by a bacteria
    • Y02A50/471The waterborne disease being caused by a bacteria the bacteria being Vibrio cholerae, i.e. Cholera
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/46Medical treatment of waterborne diseases characterized by the agent
    • Y02A50/468The waterborne disease being caused by a bacteria
    • Y02A50/478The waterborne disease being caused by a bacteria of the genus Legionella, i.e. Legionellosis or Legionnaires' disease

Abstract

本发明提供了用于涂覆一个或多个微突出物的制剂,其减小或最小化平衡离子从涂层的丧失以便实现pH稳定化的制剂。 The present invention provides a formulation for coating one or more microprojections, which reduces or minimizes the loss of counterion from the coating in order to achieve a stable pH of the formulation.

Description

含有不挥发性平衡离子的用于经涂覆的微突出物的制剂 Microprojections formulation containing a non-volatile counter ion for coated

发明领域 Field of the Invention

[0001] 本发明涉及施用和增强试剂跨过皮肤的经皮递送。 [0001] The present invention relates to administering and enhancing transdermal delivery of agents across the skin. 更具体地,本发明涉及使用皮肤穿刺微突出物(microprojection)通过角质层施用生物活性剂的经皮药物递送系统,所述微突出物具有所述生物活性剂的干燥涂层。 More particularly, the present invention relates to the use of skin piercing microprojections (microprojection) transdermal drug delivery systems administered biologically active agent through the stratum corneum, said microprojection dried coating having said biologically active agent. 当微突出物刺穿患者的皮肤并且患者的组织液接触并溶解活性剂时,实现所述试剂的递送。 When the microprojections pierce the skin of a patient and the patient's interstitial fluid contacts and dissolves the active agent to achieve the agent delivery. 更特别地,涉及涂层制剂,其抵抗涂层的PH改变并且在微突出物刺穿皮肤后促进涂层的溶解。 More particularly, it relates to the coating formulation, a coating which is resistant to change and PH microprojection promote dissolution of the coating after piercing the skin.

[0002] 发明背景 [0002] Background of the Invention

[0003] 经口或者通过注射可以最常规地施用药物。 [0003] Most conventional orally or may be administered the drug by injection. 不幸地,许多药物当经口施用时完全无效或者功效彻底降低,因为它们不被吸收或者进入血流前受到不利影响并从而不具有所希望的活性。 Unfortunately, many drugs are completely ineffective or drastically reduce the efficacy when administered orally because they are not absorbed or are adversely affected before entering the bloodstream and thus do not have the desired activity. 另一方面,药物向血流的直接注射虽然在施用期间可以保证不改变药物,但是是困难的、不方便的、痛苦或者不舒服的方法,有时导致很差的患者顺从性。 On the other hand, the direct injection of the drug into the bloodstream, although during the application can guarantee that the drug does not change, but it is difficult, inconvenient, painful or uncomfortable way, sometimes resulting in poor patient compliance.

[0004] 因此,原则上,经皮递送提供了施用药物的方法,否则所述药物将需要通过皮下注射或者静脉内输注递送。 [0004] Thus, in principle, transdermal delivery provides a method for administering a drug, said medicament would otherwise need to be delivered via hypodermic injection or intravenous infusion. 经皮药物递送提供了这些方面的改进。 Transdermal drug delivery offers improvements in these areas. 当与经口递送比较时,经皮递送避免了消化道的恶劣环境,绕过了胃肠药物代谢,减小了首过效应(first-passeffect),并避免了消化酶和肝脏酶的可能的失活作用。 When compared to oral delivery, transdermal delivery avoids the harsh environment of the digestive tract, bypasses gastrointestinal drug metabolism, reduces first-pass effect (first-passeffect), and to avoid possible digestive and liver enzymes inactivation. 相反地,在经皮施用期间消化道不受到药物的影响。 Conversely, the digestive tract during percutaneous administration is not influenced by the medication. 实际上,许多药物如阿司匹林对消化道具有不利影响。 In fact, many drugs such as aspirin have an adverse effect on the digestive tract. 然而,在许多情况中,通过被动经皮途径的许多试剂的递送速率或者通量受到太大限制,以致于不能在治疗上有效。 However, in many cases, the rate of delivery of agent by a number of passive transdermal route is too large or restricted by the flux, so as to not be effective in the treatment.

[0005] 词语“经皮”在本文中作为一般术语使用,指试剂穿过皮肤层。 [0005] The term "transdermal" as a general term used herein, refers to an agent through the skin layer. 词语“经皮”指通过皮肤递送试剂(如治疗剂,如药物)到局部组织或者全身循环系统,而不相当大地切割或者穿刺皮肤,如用手术刀切割或者用皮下针穿刺皮肤。 The word "transdermal" refers to delivery agent (e.g., a therapeutic agent, such as a drug) to the local tissue or systemic circulatory system through the skin, without a considerable cut or pierce the skin, such as cutting with a surgical knife or needle subcutaneously skin. 经皮试剂递送包括通过被动扩散以及通过外部能源包括电(例如,离子电渗疗法)和超声(例如,超声药物透入疗法)递送。 Transdermal agent delivery includes delivery via passive diffusion as well as by external energy sources including electricity (e.g., iontophoresis) and ultrasound (e.g., ultrasonic therapy drug penetration) delivery. 尽管药物跨过角质层和表皮扩散,但是通过角质层扩散的速率通常是限制步骤。 Although the drug diffusion across the stratum corneum and epidermis, but the rate of diffusion through the stratum corneum is often the limiting step. 为了实现治疗剂量,许多化合物需要比通过简单被动经皮扩散可以实现的递送速率更高的递送速率。 In order to achieve a therapeutic dose, a number of compounds require higher delivery rates than by simple passive transdermal diffusion delivery rate can be achieved. 当与注射比较时,经皮试剂递送消除了相关疼痛并减小了感染的可能性。 When compared to injections, transdermal agent delivery eliminates the associated pain and reduces the possibility of infection.

[0006] 理论上,试剂施用的经皮途径在许多治疗蛋白质的递送中是有利的,因为蛋白质易受胃肠降解并且显示出弱的胃肠吸收,并且经皮装置比注射更容易让患者接受。 [0006] Theoretically, the transdermal route of agent administration is the delivery of many therapeutic proteins, it is advantageous, because the protein is susceptible to gastrointestinal degradation and exhibit weak gastrointestinal absorption, and transdermal devices than the injection easier for patients . 然而,医学上有用的肽和蛋白质的经皮通量由于这些分子的大尺寸/分子量而通常不足以在治疗上有效。 However, a useful transdermal flux of medically peptides and proteins due to the large size of these molecules / molecular weight usually sufficiently effective therapeutically. 通常,递送速率或者通量不足以产生所希望的效果或者试剂在达到靶位点之前,例如,在患者的血流中就被降解。 Typically, delivery rate or flux is insufficient to produce the desired effect or the agent prior to reaching the target site, e.g., in the patient's bloodstream was degraded.

[0007] 经皮药物递送系统通常依赖于被动扩散来施用药物,而主动经皮药物递送系统依赖外部能源(例如,电)来递送药物。 [0007] The transdermal drug delivery systems generally rely on passive diffusion to administer the drug while active transdermal drug delivery systems rely on an external energy source (e.g., electricity) to deliver the drug. 被动经皮药物递送系统更常见。 Passive transdermal drug delivery systems are more common. 被动经皮系统具有药物忙库(reservoir),其含有适于接触皮肤的高浓度药物,在那里药物通过所述皮肤扩散并进入患者的身体组织或者血流。 Passive transdermal systems have a drug library busy (Reservoir), which contains a high concentration of drug adapted to contact the skin, diffusion of drug through the skin and into the patient, where the body tissue or blood. 经皮药物通量取决于皮肤的状况、药物分子的大小和物理/化学性质,和穿过皮肤的浓度梯度。 The transdermal drug flux depends on the condition of the skin, the drug molecule size and physical / chemical properties, and the concentration gradient through the skin. 因为皮肤对许多药物的低透性,所以经皮递送具有有限的应用。 Because of the low skin permeability to many drugs, transdermal delivery therefore it has limited application. 该低透性主要归因于角质层,其是最外面的皮肤层,由充满脂双层包围的角质纤维的扁平死亡细胞(角质形成细胞)组成。 This low permeability is attributed primarily to the stratum corneum, which is the outermost layer of the skin, flat dead cells filled with keratin fibers of a lipid bilayer surrounding (keratinocytes) composition. 脂双层的该高度有序的结构赋予了角质层的相对不透性特征。 The highly ordered structure of the lipid bilayers confers a relatively impermeable characteristics of the stratum corneum.

[0008] 主动运输系统使用外部能源帮助药物流过角质层。 [0008] active transport systems use an external energy source to help the drug flow through the stratum corneum. 经皮药物递送的一种此类增强作用称作“电转运”。 A transdermal drug delivery enhancement such as "electrotransport." 该机制使用电位,其导致应用电流帮助试剂通过身体表面,如皮肤的转运。 This mechanism uses electric potential, which results in a current applied through the body surface help agent, such as transport of the skin. 其他主动运输系统使用超声(超声药物透入疗法)和热作为外部能源。 Other active transport systems use ultrasound (phonophoresis drugs) and heat as the external energy.

[0009] 还有许多尝试来机械穿透或者破坏最外皮肤层,从而产生进入皮肤的途径,以便增强经皮递送的试剂的量。 [0009] There are many attempts to mechanically penetrate or disrupt the outermost skin layers, thereby creating pathways into the skin in order to enhance transdermal agent delivery amount. 称作划痕器的早期接种装置通常具有许多尖齿或者针头,其应用于皮肤并在所应用的区域产生划痕或者产生小切口。 Early vaccination devices known as scarifiers generally have a number of tines or needles, which is applied to the skin and scratches in the region of the applied or generated small incision. 将疫苗局部应用于皮肤(如授予Rabenau的美国专利号5,487,726)或者作为湿润液体应用于划痕器尖齿(如授予Galy的美国专利号4,453,926或者授予Chacornac的4,109,655或者授予Kravitz的3,136,314)。 The vaccine topical application to the skin (e.g., granted U.S. Patent No. 5,487, 726 Rabenau) or as a liquid applied to the wet streaker tines (granted as U.S. Patent No. 4,453,926 Galy granted Chacornac, or 4, Kravitz 109,655 or grant of 3,136,314). 已经提出将划痕器用于经皮疫苗递送,这部分是因为为了有效免疫患者,仅需要将非常小量的疫苗递送到皮肤。 The scratches have been proposed for transdermal vaccine delivery, in part because immune to the patient an effective, would need only a very small amount of vaccine delivered to the skin. 此外,所递送的疫苗的量不是特别关键的,因为过量与最小量都实现满意的免疫。 In addition, the amount of vaccine delivered is not particularly critical, because with a minimal amount of excess have achieved satisfactory immunity. 然而,使用划痕器递送药物的一个严重缺点是难以确定经皮药物通量和所递送的剂量。 However, a serious disadvantage in using a scarifier to deliver a drug is the difficulty in determining the transdermal drug flux and the dose delivered. 还由于皮肤的弹性、变形和反弹性质偏转和抵抗穿刺,所以小穿刺元件通常不均匀地穿过皮肤和/或皮肤穿透后被擦除试剂的液体涂层。 Also due to the elasticity of the skin, deformation and rebound properties to deflect and resist puncturing, the tiny piercing elements generally unevenly through the skin and / or skin penetration erased after a liquid coating agent. 此外,由于皮肤的自身愈合过程,所以从角质层除去穿刺元件后,在皮肤中产生的孔或者裂缝倾向于闭合。 Further, since the self-healing process of the skin, the stratum corneum is removed from the pricking element, resulting in the skin tend to close the hole or crack. 从而,在这些元件穿透皮肤后,皮肤的弹性性质除去应用于小穿刺元件的活性剂涂层。 Thus, after these elements to penetrate the skin, the elastic properties of the skin to remove the active agent coating is applied to small piercing element. 此外,通过穿刺元件形成的小裂缝在除去所述装置后快速愈合,从而限制试剂通过穿刺元件产生的通路经过,且这又限制了此类装置的经皮通量。 In addition, small cracks formed by the piercing elements heal quickly after removal of the device, thus limiting the passage through the agent produced by the puncturing elements, and this in turn limits the transdermal flux of such devices.

[0010] 使用小皮肤穿刺元件增强经皮药物递送的其他装置在欧洲专利EP0407063A1、授予Godshall等人的美国专利号5,879,326、授予Ganderton等人的美国专利号3,814,097、授予Gross等人的美国专利号5,279,544、授予Lee等人的美国专利号5,250,023、授予Gerstel等人的美国专利号3,964, 482、授予Kravitz等人的再颁专利(Reissue) 25,637和PCT 公开号W 96/37155、W096/37256、W096/17648、W097/03718、WO 98/11937、WO98/00193,W097/ 48440,W097/4844I,WO 97/48442、WO 98/00193、TO99/64580、W098/28037、WO 98/29298和WO 98/29365中描述,将所有这些文献都完整引用作为参考。 [0010] Using a small skin piercing elements to enhance transdermal drug delivery devices other in European Patent EP0407063A1, granted to Godshall et al U.S. Patent No. 5,879, 326, granted to Ganderton et al., U.S. Patent No. 3,814,097, granted Gross et al., US Patent No. 5,279,544, issued to Lee et al., US Patent No. 5,250,023, granted to Gerstel, et al., US Patent No. 3,964, 482, granted to Kravitz, et al Reissue Patent ( Reissue) 25,637, and PCT Publication No. W 96/37155, W096 / 37256, W096 / 17648, W097 / 03718, WO 98/11937, WO98 / 00193, W097 / 48440, W097 / 4844I, WO 97/48442, WO 98 / 00193, TO99 / ​​64580, W098 / 28037, WO 98/29298 and WO 98/29365 are described, all of which are incorporated by reference in full. 这些装置使用多种形状和大小的穿刺元件来穿刺皮肤的最外层(即,角质层)。 These devices use piercing elements of various shapes and sizes to pierce the skin of the outermost layer (i.e., stratum corneum). 这些参考文献中公开的穿刺元件通常从薄的平坦部件(如垫或者片)垂直延伸。 Piercing elements disclosed in these references generally planar member from a thin (e.g., a pad or sheet) extends vertically. 这些装置的一些中的穿刺元件非常小,一些具有仅约25-400 μ m的尺寸(S卩,微刀片(microblade)长度和宽度)和仅约5-50 μ m的微刀片厚度。 Some of these devices is very small piercing element, having a size of some microblade thickness of only about 25-400 μ m of (S Jie, microblade (MicroBlade) length and width) of only about 5-50 μ m and the. 这些小的穿刺/切割元件在角质层产生相应的小的微裂缝(microslit)/微切口(microcut)以增强通过微裂缝/微切口的经皮试剂递送。 These small piercing / cutting elements produces a corresponding small microcracks (microslit) in the stratum corneum / tiny incision (Microcut) to enhance through microcracks / microincisional transdermal agent delivery.

[0011] 通常,这些系统包括用于保持药物的贮库和用于将贮库的药物通过角质层转移,如通过装置自身的中空尖齿转移的递送装置。 [0011] Generally, these systems include a reservoir for holding the drug and a drug depot for transfer through the stratum corneum, such as the delivery device transferred through hollow tines of the device itself. 另一备选方案是提供微突出物自身上的含有活性剂的涂层。 Another alternative is to provide a microprojection coating containing the active agent itself. 此类方法已经公开在公开的美国专利申请号2002/0132054、2002/0193729、2002/0177839和2002/0128599,将它们引入本文作为参考。 Such methods have been disclosed in U.S. Patent Application Publication No. 2002 in / 0132054,2002 / 0193729,2002 / 0177839 and 2002/0128599, incorporated herein by reference in their.

[0012] 使用微突出物装置经皮递送涂覆在微突出物上的试剂赋予了许多益处。 [0012] A microprojection transdermal delivery device agent coated on the microprojections confers a number of benefits. 然而,用于涂覆微突出物的一些制剂不能实现穿刺皮肤后容易溶解的涂层。 However, some formulation for coating microprojections piercing can not be achieved readily soluble coating of the skin.

[0013] 因此,本发明的目的是提供具有提高的溶解性的涂层。 [0013] Accordingly, an object of the present invention is to provide a coating having improved solubility.

[0014] 本发明的另一目的是提供稳定涂层的pH并且可以增加不带电的生物活性剂的量的涂层,所述生物活性剂在生理溶液溶解性较小。 [0014] Another object of the present invention is to provide a pH and stable coating can increase the amount of uncharged bioactive agent coating, the bioactive agent is less soluble in a physiological solution.

[0015] 发明概述 [0015] Summary of the Invention

[0016] 根据上面的目的和下文将提及和变得明显的目的,经皮递送根据本发明的生物活性剂的装置和方法通常包含具有微突出物部件(或系统)的递送系统,所述微突出物部件(或系统)包括适宜通过角质层穿刺到下面的表皮层或者表皮和真皮层的至少一个微突出物(或其阵列)。 [0016] The above mentioned objects and below objects and become apparent, transdermal delivery devices and methods according to the bioactive agent of the present invention generally comprises a delivery system having a microprojection member (or system), the microprojection member (or system) comprising suitable to puncture the underlying epidermis layer, or epidermis and dermis layers of the stratum corneum by at least one microprojection (or array thereof). 在一个实施方案中,所述微突出物包括生物相容的涂层,其中具有至少一种生物活性剂。 In one embodiment, the microprojection including a biocompatible coating composition, wherein at least one biologically active agent.

[0017] 同样,本发明的一个实施方案是用于涂覆经皮递送装置的组合物,所述经皮递送装置具有角质层穿刺微突出物,所述组合物包含生物活性剂制剂和不挥发性平衡离子,其中所述制剂当干燥时PH稳定性和溶解性增加。 [0017] Similarly, an embodiment of the present invention is a composition for coating a transdermal delivery device, transdermal delivery device has the stratum corneum piercing microprojections, said composition comprising a biologically active agent formulation and a non-volatile ion balance, wherein said formulation when dried PH increased stability and solubility.

[0018] 适宜的生物活性剂包括所有主要治疗领域的治疗剂,包括,但不限于:抗感染药,如抗生素和抗病毒剂;镇痛药,包括芬太尼、舒芬太尼、雷米芬太尼、丁丙诺啡和镇痛药组合;麻醉剂;厌食剂;抗关节炎药;止喘药,如特布他林;抗惊厥剂;抗抑郁药;抗糖尿病剂;止泻药;抗组胺药;消炎药;抗偏头痛制剂;抗运动病制剂,如东茛菪碱和奥丹西隆;止恶心药;抗瘤剂;抗帕金森综合征药物;止痒剂;抗精神病药;退热药;镇痉剂,包括胃肠和泌尿镇痉剂;抗胆碱能药;拟交感神经药;黄嘌呤衍生物;心血管制剂,包括钙通道阻断剂,如硝苯地平;β-阻断剂;β激动剂,如多巴酚丁胺和利托君;抗心律不齐剂;抗高血压药,如阿替洛尔;ACE抑制剂,如雷尼替丁;利尿剂;血管舒张剂,包括全身、冠状、外周和脑血管舒张剂;中枢神经系统刺激 [0018] Suitable biologically active agents include therapeutic agents in all the major therapeutic areas including, but not limited to: anti-infectives such as antibiotics and antiviral agents; analgesics, including fentanyl, sufentanil, Remy fentanyl, buprenorphine and analgesic combinations; anesthetics; anorectic agents; antiarthritics; antiasthmatics such as terbutaline; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; anti histamine drugs; anti-inflammatory agents; anti-migraine preparations; anti-motion sickness preparations such as scopolamine and ondansetron; antinauseants; antineoplastic agents; anti-parkinsonism drugs; antipruritic agents; antipsychotics ; antipyretics; antispasmodics including gastrointestinal and urinary antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers such as nifedipine; β- blockers; beta] agonists, such as dobutamine and ritodrine; antiarrhythmic agents; antihypertensives, such as atenolol; the ACE inhibitors such as ranitidine; diuretics ; vasodilators, including systemic, coronary, peripheral and cerebral vasodilator; central nervous system stimulants 剂;咳嗽和感冒制剂;减充血剂;诊断剂;激素,如甲状旁腺激素;安眠药;免疫抑制剂;肌肉松驰剂;抗副交感神经药;拟副交感神经药;前列腺素;蛋白质;肽;精神兴奋剂;镇静药;和安定剂。 Agent; cough and cold preparations; decongestants; diagnostic agents; hormones, such as parathyroid hormone; hypnotics; immunosuppressant; muscle relaxants; parasympatholytics; parasympathomimetic agents; prostaglandin; protein; peptides; psychostimulants; sedatives; and tranquilizers. 其他适宜的试剂包括血管收缩剂、抗愈合剂和途径开放调节剂。 Other suitable agents include vasoconstrictors, anti-healing agents and pathway patency modulators.

[0019] 试剂的其他特定实例包括,但不限于,生长激素释放激素(GHRH)、生长激素释放因子(GHRF)、胰岛素、insultropin、降钙素、奥曲肽、内啡肽、TRN、NT_36(化学名称:N-[[(s)-4-氧代-2-氮杂环丁基]羰基]-L-组氨酰-L-脯氨酰胺)、lipreCin、垂体激素(例如,HGH、HMG、醋酸去氨加压素,等等)、卵泡类黄体素、aANF、生长因子,如生长因子释放因子(GFRF)、bMSH、GH、促生长素抑制素、缓激肽、促生长素、血小板衍生生长因子释放因子、天冬酰胺酶、硫酸博来霉素、木瓜凝乳蛋白酶、缩胆囊素、绒毛膜促性腺激素、促红细胞生成素、依前列醇(血小板聚集抑制剂)、胰高血糖素、HCG、水蛭肽(hirulog)、透明质酸酶、干扰素α、干扰素β、干扰素Y、白细胞介素、白细胞介素-10 (IL-10)、促红细胞生成素(EPO)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、粒细胞集落刺激因子(G-CSF)、胰高血糖素 [0019] Specific examples of other agents include, but are not limited to, growth hormone releasing hormone (GHRH), growth hormone releasing factor (GHRF), insulin, insultropin, calcitonin, octreotide, endorphin, TRN, NT_36 (chemical name : N - [[(s) -4- oxo-2-azetidinyl] carbonyl] -L- histidyl -L-prolinamide), lipreCin, pituitary hormones (e.g., HGH, HMG, acetate desmopressin, etc.), follicle-based progesterone, AANF, growth factors, such as growth factor releasing factor (GFRF), bMSH, GH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor releasing factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, HCG, hirulog (hirulog,), hyaluronidase, interferon [alpha], interferon beta], interferon Y, interleukin, interleukin -10 (IL-10), erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), glucagon 促黄体生成激素释放激素(LHRH)、LHRH类似物(如性瑞林、醋酸亮丙瑞林、布噻来灵、曲普瑞林、高那瑞林和napfarelin、促卵泡激素(尿促卵泡素(urofollitropin) (FSH)和LH))、催产素、链激酶、组织纤溶酶原激活物、尿激酶、血管加压素、脱氨基[Val4,D-ArgS]精氨酸血管加压素、去氨加压素、促肾上腺皮质激素(ACTH)、ACTH类似物,如ACTH(l-24)、ANP、ANP清除抑制剂、血管紧张肽II拮抗剂、抗利尿激素激动剂、缓激肽拮抗剂、ceredase, CST、降钙素基因相关肽(CGRP)、脑啡肽、FAB片段、IgE肽抑制因子、IGF-1、神经营养因子、集落刺激因子、甲状旁腺激素和激动剂、甲状旁腺激素拮抗剂、甲状旁腺激素(PTH)、PTH类似物,如ΡΤΗ(1-34)、前列腺素拮抗剂、喷替替特、C蛋白、S蛋白、肾素抑制剂、胸腺素α-1、溶栓剂、TNF、血管加压素拮抗剂类似物、α -1抗胰蛋白酶(重组的)和TGF-β。 Luteinizing hormone releasing hormone (LHRH), LHRH analogs (such as goserelin, leuprolide, thiophene cloth to Ling, triptorelin, gonadorelin high and napfarelin, follicle stimulating hormone (UrofoUitropin (urofollitropin ) (of FSH) and LH)), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, deamination [Val4, D-argS] arginine vasopressin, desmopressin vasopressin, adrenocorticotropic hormone (ACTH), ACTH analogs such as ACTH (l-24), ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, bradykinin antagonists, ceredase, CST, calcitonin gene related peptide (of CGRP), enkephalins, FAB fragments, IgE peptide inhibitors, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, parathyroid hormone (PTH), PTH analogs, such as ΡΤΗ (1-34), prostaglandin antagonists, for Laid pentetate, C protein, S protein, renin inhibitors, thymosin α-1, thrombolytics, TNF, vasopressin antagonist analogs, α -1-antitrypsin (recombinant), and TGF-β.

[0020] 生物活性剂还可以包含疫苗,包括病毒和细菌、基于蛋白质的疫苗、基于多糖的疫苗、基于核酸的疫苗和其他抗原剂。 [0020] The biologically active agent may also comprise a vaccine, including viruses and bacteria, protein-based vaccines, polysaccharide-based vaccine, and a vaccine based on nucleic acids of other antigens. 适宜的抗原剂包括,但不限于,蛋白质、多糖缀合物、寡糖和脂蛋白形式的抗原。 Suitable antigenic agents include, but are not limited to, proteins, polysaccharide conjugates, oligosaccharides, and lipoproteins in the form of an antigen. 这些亚基疫苗包括百日咳博德特氏菌(Bordetella pertussis)(重组的PT accince-无细胞的)、破伤风梭菌(Clostridium tetani)(纯化的,重组的)、白喉棒杆菌(Corynebacterium diptheriae)(纯化的,重组的)、巨细胞病毒(糖蛋白亚基)、A组链球菌(糖蛋白亚基、糖缀合物A组多糖与破伤风类毒素,M蛋白质/肽连接到毒性亚基载体,M蛋白质,多价型特异的表位,半胱氨酸蛋白酶,C5a肽酶)、乙型肝炎病毒(重组Pre S1、Pre-S2、S、重组核心蛋白质)、丙型肝炎病毒(重组表达的表面蛋白质和表位)、人乳头瘤病毒(衣壳蛋白,TA-GN重组蛋白质L2和E7 [来自HPV-6]、来自HPV-1l的MED1-501 重组VLP L1、四价重组BLP LI [来自HPV-6]、HPV-1U HPV-16 和HPV-18、LAMP-E7 [来自HPV-16])、侵肺军团菌(Legionella pneumophila)(纯化的细菌表面蛋白质)、脑膜炎萘瑟氏球菌(Neisseria meningitides)(与破伤风类毒素的糖缀合物)、铜绿假单胞菌(Pseudomonas These subunit vaccines include Bordetella pertussis (Bordetella pertussis) (recombinant PT accince- acellular), Clostridium tetani (Clostridium tetani) (purified, recombinant), Corynebacterium diphtheriae (Corynebacterium diptheriae) ( the purified, recombinant), cytomegalovirus (glycoprotein subunit), group a streptococcus (glycoprotein subunit, glycoconjugate group a polysaccharide with tetanus toxoid, M protein / peptide carrier coupled to toxic subunit , M protein, multivalent type-specific epitopes, cysteine ​​protease, of C5a peptidase), hepatitis B virus (recombinant Pre S1, Pre-S2, S, recombinant core protein), hepatitis C virus (recombinant surface proteins and epitopes), human papillomavirus (capsid protein, TA-GN recombinant protein L2 and E7 [from HPV-6], MED1-501 from HPV-1l recombinant VLP L1, tetravalent recombinant BLP LI [ from HPV-6], HPV-1U HPV-16 and HPV-18, LAMP-E7 [from HPV-16]), Legionella pneumophila (Legionella pneumophila) (purified bacterial surface protein), meningitis naphthalene Joseph meningitidis (Neisseria meningitides) (tetanus toxoid glycoconjugate), Pseudomonas aeruginosa (of Pseudomonas aeruginosa)(合成肽)、风疫病毒(合成肽)、肺炎链球菌(Streptococcuspneumoniae)(缀合脑膜炎球菌B OMP 的糖缀合物[1、4、5、6B、9N、14、18C、1叭、23?]、缀合0^197的糖缀合物[4、68、抑、14、18(:、19?、23?]、缀合0^1970的糖缀合物[1、4、5、68、抑、14、18(:、19卩、23卩]、苍白密螺旋体(Treponema pallidum)(表面脂蛋白)、水痘带状疱疹病毒(亚基,糖蛋白)和霍乱弧菌(Vibrio cholerae)(缀合脂多糖)。 aeruginosa) (synthetic peptide), wind disease virus (synthetic peptide), Streptococcus pneumoniae (Streptococcuspneumoniae) (conjugated to meningococcal B OMP glycoconjugates [1,4,5,6B, 9N, 14,18C, 1 a pair, 23], conjugation glycoconjugate 0 ^ 197 [4,68, suppression, 14, 18 (:?, 19, 23], conjugation glycoconjugate 0 ^ 1970 [1,4?? , 5, 68, suppressing, 14, 18 (:, 19 Jie, Jie 23], Treponema pallidum (Treponema pallidum) (surface lipoproteins), varicella zoster virus (subunit, glycoproteins), and Vibrio cholerae ( Vibrio cholerae) (conjugated LPS).

[0021] 完整病毒或细菌包括,但不限于,弱化或者杀死的病毒,如巨细胞病毒、乙型肝炎病毒、丙型肝炎病毒、人乳头瘤病毒、风疹病毒和水痘带状疱疹病毒,弱化或杀灭的细菌,如百日咳博德特氏菌、破伤风梭菌、白喉棒杆菌、A组链球菌、侵肺军团菌、脑膜炎萘瑟氏球菌、铜绿假单胞菌、肺炎链球菌、苍白密螺旋体和霍乱弧菌,和它们的混合物。 [0021] The whole virus or bacteria include, without limitation, weakened or killed viruses such as cytomegalovirus, hepatitis B virus, hepatitis C virus, human papillomavirus, rubella virus, and varicella zoster virus, weakening or killed bacteria such as Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheriae, a group streptococcus, Legionella pneumophila, meningitis naphthyl Joseph meningitidis, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Treponema pallidum, Vibrio cholerae, and mixtures thereof.

[0022] 额外的通过商业途径可得到的含有抗原剂的疫苗包括,但不限于,流感疫苗、莱姆病疫苗、狂犬病疫苗、麻疹疫苗、腮腺炎疫苗、禽痘疫苗、天花疫苗、肝炎疫苗、百日咳疫苗和白喉(diptheria )疫苗。 [0022] Additional vaccine containing the antigen agent commercially available include, but are not limited to, flu vaccines, Lyme disease vaccine, rabies vaccine, measles vaccine, mumps vaccine, a fowl pox vaccine, smallpox vaccine, hepatitis vaccine, diphtheria and pertussis vaccine (diptheria) vaccines.

[0023] 包含核酸的疫苗包括,但不限于,单链和双链核酸,如超螺旋的质粒DNA ;线性质粒DNA ;粘粒;细菌人工染色体(BAC);酵母人工染色体(YAC);哺乳动物人工染色体JPRNA分子,如mRNA。 [0023] Vaccines comprising nucleic acids include, but are not limited to, single and double stranded nucleic acids, supercoiled plasmid DNA; linear plasmid DNA; cosmids; bacterial artificial chromosome (the BAC); yeast artificial chromosomes (YACs); mammal artificial chromosome JPRNA molecules, such as mRNA. 核酸的大小可以最长达数千碱基。 The size of the nucleic acid can be up to several kilobases. 此外,在本发明的某些实施方案中,核酸可以与蛋白剂偶联或者可以包括一种或多种化学修饰,如硫代磷酸酯部分。 Further, in certain embodiments of the invention, the nucleic acid can be conjugated to the protein or agent may include one or more chemical modifications, such as phosphorothioate moieties. 核酸的编码序列包含抗原序列,希望针对所述抗原产生免疫应答。 The coding sequence of a nucleic acid sequence comprising an antigen, an immune response against the desired antigen. 此外,对于DNA,启动子和多腺苷酸化序列也整合到疫苗构建体中。 Further, respect to DNA, promoter and polyadenylation sequences are also incorporated into the vaccine construct. 可以编码的抗原包括传染病的所有抗原性成分、病原体以及癌抗原。 May encode antigens include all antigenic components of infectious pathogens and cancer antigens. 从而,所述核酸可以应用于例如,传染病、癌症、变态反应、自身免疫病和炎性疾病领域。 Thus, the nucleic acid may be applied, for example, cancer, allergy, autoimmune disease, inflammatory disease and infectious disease.

[0024] 与疫苗抗原一起可以组成疫苗的适宜的免疫应答增强性佐剂包括磷酸铝凝胶;氢氧化招;藻类葡聚糖:b-葡聚糖;霍乱毒素B亚基;平均值为x = 8和y = 205的CRL1005:ABA嵌段聚合物;Y菊糖:线性(不分枝的)β-D(2-> I)聚呋喃果糖氧基(polyfructofuranoxyl)-a_D-葡萄糖;Gerbu 佐剂:N_ 乙酰葡糖胺-(bl_4)-N_ 乙酰胞壁酰-L-丙氨酰-D-谷氨酰胺(GMDP)、二甲基二(十八烷基)氯化铵(DDA)、L-脯氨酸锌盐络合物(Zn-Pro-8)、咪喹莫特(1_(2_甲基丙基)_1Η_咪唑并[4,5-C]喹啉-4-胺;ImmTlier0:N_ 乙酰葡糖胺基(acetyglucoaminyl)-N-乙 [0024] Suitable adjuvants to enhance immune responses and may together form a vaccine antigen vaccine include aluminum phosphate gel; hydroxide strokes; algal glucan: b- glucan; cholera toxin B subunit; average value of x = 8 and y = 205 to CRL1005: ABA block polymer; the Y inulin: linear (unbranched) β-D (2-> I) poly-oxy-fructopyranose (polyfructofuranoxyl) -a_D- glucose; Gerbu adjuvant agents: N_ acetylglucosamine - (bl_4) -N_ acetyl muramyl-alanyl -D- -L- glutamine (GMDP), dimethyl (octadecyl) ammonium chloride (DDA), L- proline zinc salt complex (Zn-Pro-8), imiquimod (1_ (2_ methylpropyl) _1Η_ imidazo [4,5-C] quinolin-4-amine; ImmTlier0: N_ acetylglucosaminyltransferase (acetyglucoaminyl) -N- b

酰胞壁酰-L-Ala-D-1soGlu-L-Ala-甘油二棕榈酸酯;MTP_PE脂质体:C59H108N6019PNa-3H20(MTP) ;Murametide:Nac-Mur-L-Ala-D-Gln-0CH3 ;Pleuran:b-葡聚糖;QS-21 ;S-28463:4-氨基-a, a_ 二甲基-1H-咪唑并[4,5_c]喹啉-1-乙醇;sclavo肽:VQGEESNDK.HCl (IL-1bi63_i7i 肽);和苏氨酰-MDP( TermurtideO):N-乙酰胞壁酰-L-苏氨酰-D-异谷氨酰胺,和白细胞介素18、IL-2、IL-12、IL-15,佐剂还包括DNA寡核苷酸,如含有CpG的寡核苷酸。 Acyloxy muramyl -L-Ala-D-1soGlu-L-Ala- glycerol dipalmitate; MTP_PE liposomes: C59H108N6019PNa-3H20 (MTP); Murametide: Nac-Mur-L-Ala-D-Gln-0CH3 ; Pleuran: b- glucan; QS-21; S-28463: 4- amino -a, a_ dimethyl -1H- imidazo [4,5_c] quinolin-1-ethanol; Sclavo peptide: VQGEESNDK.HCl (IL-1bi63_i7i peptide); and threonyl -MDP (TermurtideO): N- acetyl muramyl -L- threonyl -D- isoglutamine, and interleukin-18, IL-2, IL-12 , IL-15, adjuvants also include DNA oligonucleotides, such as oligonucleotides containing CpG. 此外,还可以使用编码免疫调节性淋巴因子的核酸序列,所述免疫调节性淋巴因子为例如IL-18、IL-2、IL-12、IL-15、IL-4、IL-10、Y干扰素和NK κ B调节信号传导蛋白质。 In addition, use may also be nucleic acid sequences encoding immunomodulatory lymphokines, said immunomodulatory lymphokines, for example, IL-18, IL-2, IL-12, IL-15, IL-4, IL-10, Y interference regulating hormone and NK κ B signaling proteins.

[0025] 通常,在本发明的所提到的实施方案中,平衡离子的量应该中和生物活性剂的电荷。 [0025] Generally, in the noted embodiments of the present invention, the amount of counterion should neutralize the charge of the biologically active agent. 在此类实施方案中,平衡离子或者平衡离子混合物以中和在制剂的pH下试剂上存在的电荷所必需的量存在。 In such embodiments, the counterion or counterion mixture is present in an amount of charges on the pH and the necessary reagents present in the formulation. 可以向肽加入过量平衡离子(作为游离酸或者盐)以控制PH和提供足够缓冲能力。 Counter ion may be added to an excess of the peptide (as the free acid or a salt thereof) to control the PH and adequate buffering capacity.

[0026] 在另一优选实施方案中,平衡离子是强酸。 [0026] In another preferred embodiment, the counterion is a strong acid. 强酸可以定义为具有至少一个低于约2的pKa。 It may be defined as at least a strong acid having a pKa less than about 2. 此类酸的实例包括盐酸、氢溴酸、硝酸、磺酸、硫酸、马来酸、磷酸、苯磺酸和甲磺酸。 Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid.

[0027] 另一优选的实施方案涉及平衡离子的混合物,其中至少一种平衡离子是强酸,并且至少一种平衡离子是低挥发性弱酸。 [0027] Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion is a strong acid and at least one counterion is a low volatility weak acid.

[0028] 另一优选实施方案涉及平衡离子的混合物,其中至少一种平衡离子是强酸,并且至少一种平衡离子是高挥发性弱酸。 [0028] Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion is a strong acid and at least one high volatility counterion is a weak acid. 挥发性弱酸平衡离子具有至少一种高于约2的pKa和在Patm下低于约50°C的熔点或者低于约170°C的沸点。 Volatile weak acid counterions having at least one pKa less than about 2 and a melting point of about boiling point of 50 ° C or below at Patm higher than about 170 ° C. 此类酸的实例包括乙酸、丙酸、戊 Examples of such acids include acetic acid, propionic acid, pentyl

酸等等。 Acid and so on.

[0029] 酸性平衡离子以中和在制剂的pH下药物上存在的正电荷所需的量存在。 [0029] The amount of the acidic counterion is present to neutralize the positive charge present on the pH of the pharmaceutical formulation desired. 可以将过量平衡离子(作为游离酸或者盐)加入药物中以控制PH和提供足够缓冲能力。 Excess counterion may be (as the free acid or a salt thereof) added to the drug to provide adequate control and PH buffering capacity.

[0030] 在本发明的一个实施方案中,涂层制剂包括至少一种抗氧化剂,其可以是螯合剂,如柠檬酸钠、柠檬酸、EDTA(乙二胺四乙酸)或者自由基清除剂,如抗坏血酸、甲硫氨酸、抗坏血酸钠,等等。 [0030] In one embodiment of the present invention, the coating formulations include at least one antioxidant, which can be a chelating agent, such as sodium citrate, citric acid, EDTA (ethylenediaminetetraacetic acid) or free radical scavengers, such as ascorbic acid, methionine, sodium ascorbate, and the like.

[0031] 在本发明的一个实施方案中,涂层制剂包括至少一种表面活性剂,其可以是两性离子的、兼性的、阳离子的、阴离子的或者非离子表面活性剂,包括但不限于,月桂酰两性基乙酸钠(sodiumlauroamphoacetate)、十二烧基硫酸钠(SDS)、十六烧基氯化卩比唳鐵(CPC)、十二烷基三甲基氯化铵(TMAC)、盐酸胱胺、氯化物、聚山梨酸酯(如Tween 20和Tween80)、其他山梨聚糖衍生物(如失水山梨糖醇月桂酸酯)和烷氧基化醇(如聚乙二醇单十二Bi 4)。 [0031] In one embodiment of the present invention, the coating formulations include at least one surfactant, which may be, facultative zwitterionic, cationic, anionic or non-ionic surfactants, including, but not limited to, , sodium lauroampho acetate (sodiumlauroamphoacetate), twelve group burning sulfate (SDS), sixteen burning yl Jie Li ratio of iron chloride (CPC), dodecyltrimethylammonium chloride (of TMAC), hydrochloric acid cystamine, chloride, polysorbates (e.g. Tween 20 and Tween 80), other sorbitan derivatives (e.g., sorbitan laurate), and alkoxylated alcohols (e.g. polyethylene glycol monolaurate Bi 4).

[0032] 在本发明的另一实施方案中,涂层制剂包括具有两亲性质的至少一种聚合物材料或者聚合物,其可以包含,但不限于,纤维素衍生物,如羟乙基纤维素(HEC)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、甲基纤维素(MC)、羟乙基甲基纤维素(HEMC)或者乙基羟基-乙基纤维素(EHEC)以及普流罗尼(pluronics)。 [0032] In another embodiment of the present invention, the coating formulations include at least one polymeric material or polymer that has amphiphilic properties, which may include, but are not limited to, cellulose derivatives such as hydroxyethyl cellulose Su (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxyethyl methyl cellulose (HEMC), or ethylhydroxy - ethyl (EHEC), and pluronics (pluronics).

[0033] 在另一实施方案中,涂层制剂包括亲水聚合物,其选自下面的组:羟乙基淀粉、葡聚糖、聚(乙烯醇)、聚(环氧乙烷)、聚(甲基丙烯酸2-羟基乙酯)、聚(正乙烯吡咯烷酮)、聚乙二醇和它们的混合物,和类似聚合物。 [0033] In another embodiment, the coating formulation includes a hydrophilic polymer selected from the following group: hydroxyethyl starch, dextran, poly (vinyl alcohol), poly (ethylene oxide), poly (2-hydroxyethyl methacrylate), poly (n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and like polymers.

[0034] 在本发明的另一实施方案中,涂层制剂包括生物相容性载体,其可以包括,但不限于,人清蛋白、生物工程化人清蛋白、聚谷氨酸、聚天冬氨酸、聚组氨酸、多硫酸戊聚糖、聚氨基酸、蔗糖、海藻糖、松三糖、棉子糖和水苏糖。 [0034] In another embodiment of the present invention, the coating formulation includes a biocompatible carrier, which may include, but are not limited to, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffinose and stachyose.

[0035] 在另一实施方案中,涂层制剂包括稳定剂,其可以包含,但不限于,非还原糖、多糖或者还原糖。 [0035] In another embodiment, the coating formulation includes a stabilizing agent, which may include, but are not limited to, non-reducing sugar, a polysaccharide or a reducing sugar. 用于本发明的方法和组合物中的适宜的非还原糖包括,例如,蔗糖、海藻糖、水苏糖或者棉子糖。 Suitable non-reducing sugars used in the methods and compositions of the present invention include, for example, sucrose, trehalose, stachyose, or raffinose. 用于本发明的方法和组合物中的适宜的多糖包括,例如,葡聚糖、可溶性淀粉、糊精和胰岛素。 Methods and compositions of the present invention suitable polysaccharides include, for example, dextran, soluble starch, dextrin, and insulin. 用于本发明的方法和组合物中的适宜的还原糖包括,例如,单糖,例如,芹菜糖、阿拉伯糖、来苏糖、核糖、木糖、洋地黄毒糖、岩藻糖、栎醇、鸡纳糖、鼠李糖、阿洛糖、阿卓糖、果糖、半乳糖、葡萄糖、古洛糖、金缕梅糖、艾杜糖、甘露糖、塔格糖等等;和二糖,如樱草糖、荚豆二糖、芸香糖、绵枣儿二糖、纤维二糖、龙胆二糖、乳糖、乳果糖、麦芽糖、蜜二糖、槐二糖和松二糖等等。 The methods and compositions used in the present invention Suitable reducing sugars include, e.g., monosaccharides, e.g., apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol , chicken satisfied, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, witch hazel, idose, mannose, tagatose, and the like; and disaccharides, such as primrose sugar, bean pods disaccharide, rutin sugar, Scilla disaccharide, cellobiose, gentian disaccharide, lactose, lactulose, maltose, melibiose, locust and pine disaccharide disaccharide and so on.

[0036] 在另一实施方案中,涂层制剂包括血管收缩剂,其可以包含,但不限于,阿米福林、咖啡氨醇、甲环戊丙胺、去氧肾上腺素、肾上腺素、苯赖加压素、茚咪唑啉、甲噻嗯唑啉、甲氧胺福林、萘唑林、盐酸异肾上腺素、异辛胺、鸟氨酸加压素、羟甲唑啉、苯福林、苯乙醇胺、苯丙醇胺、环己丙甲胺、假麻黄碱、四氢唑啉、萘胺唑啉、庚胺、麝草唑啉、血管加压素、丁苄唑啉和它们的混合物。 [0036] In another embodiment, the coating formulation includes a vasoconstrictor, which can comprise, without limitation, amidephrine, coffee sphingosine, cyclopentyl methyl amine, phenylephrine, epinephrine, benzene Lai vasopressin, indene imidazoline, oxazoline A thiazole ah, methoxyamine phenylephrine, naphthalene cefazolin, epinephrine hydrochloride isopropyl, iso-octylamine, ornithine vasopressin, oxymetazoline, phenylephrine, benzene ethanolamine, phenylpropanolamine, propylhexedrine cycloalkyl, pseudoephedrine, tetrahydrozoline, naphthylamine oxazoline, heptyl amine, oxazoline musk grass, vasopressin, xylometazoline and mixtures thereof. 最优选的血管收缩剂包括肾上腺素、萘唑林、四氢唑啉、茚咪唑啉、甲噻嗯唑啉、萘胺唑啉、麝草唑啉、羟甲唑啉和丁苄唑啉。 The most preferred vasoconstrictors include epinephrine, naphthalene cefazolin, tetrahydrozoline, indene imidazoline, oxazoline ah A thiazole, oxazoline naphthylamine, musk grass oxazoline, oxymetazoline and xylometazoline.

[0037] 在本发明的另一实施方案中,涂层制剂包括至少一种“途径开放调节剂”,其可以包含,但不限于,渗透性试剂(例如,氯化钠)、两性离子化合物(例如,氨基酸)和消炎药,如倍他米松21-磷酸二钠盐、醋酸去炎松21-磷酸二钠、盐酸氢可他酯、氢化可的松21-磷酸二钠盐、甲基氢化泼尼松21-磷酸二钠盐、甲基氢化泼尼松21-琥珀酸钠盐、对氟米松磷酸酯二钠和强的松龙21-琥珀酸钠盐,和抗凝血剂,如柠檬酸、柠檬酸盐(例如,柠檬酸钠)、硫酸糊精钠(dextrin sulfatesodium)、阿司匹林和EDTA。 [0037] In another embodiment of the present invention, the coating formulations include at least one "pathway patency modulator", which can comprise, without limitation, osmotic agents (e.g., sodium chloride), zwitterionic compounds ( For example, amino acids), and anti-inflammatory agents, such as betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21- disodium phosphate, hydrocortamate hydrochloride him esters, hydrocortisone 21-phosphate disodium salt, methyl hydrogen splashed prednisolone 21-phosphate disodium salt, methylprednisolone 21-succinate sodium salt, paramethasone disodium phosphate and fluoride prednisolone 21-succinate sodium salt, and anticoagulants, such as citric acid , citrate (e.g., sodium citrate), dextrin sulfate sodium (dextrin sulfatesodium), aspirin and EDTA.

[0038] 在本发明的再一个实施方案中,涂层制剂包括增溶/络合剂,其可以包含α -环糊精、β -环糊精、Y -环糊精、葡糖基-α -环糊精、麦芽糖基-α -环糊精、葡糖基-β -环糊精、麦芽糖基_ β _环糊精、轻丙基_ β _环糊精、2-轻丙基环糊精、2-轻丙基-γ-环糊精、羟乙基-β -环糊精、甲基-β -环糊精、磺丁基醚-α -环糊精、磺丁基醚-β -环糊精和磺丁基醚-Y-环糊精。 [0038] In a further embodiment of the present invention, the coating formulation includes a solubilising / complexing agent, which may comprise α - cyclodextrin, β - cyclodextrin, Y - cyclodextrin, glucosyl -α - cyclodextrin, maltosyl [alpha - cyclodextrin, glucosyl-yl [beta] -D - cyclodextrin, maltosyl-beta] _ _ cyclodextrin, propyl light _ _ beta] -cyclodextrin, 2-propyl-cyclodextrin light fine, light-propyl 2- -γ- cyclodextrin, hydroxyethyl -β - cyclodextrin, methyl -β - cyclodextrin, sulfobutyl ether -α - cyclodextrin, sulfobutyl ether [beta] -D - -Y- cyclodextrin and sulfobutyl ether cyclodextrin. 最优选的增溶/络合剂为环糊精、羟丙基环糊精、2-羟丙基-β -环糊精和磺丁基醚7 β-环糊精。 The most preferred solubilising / complexing agent is a cyclodextrin, hydroxypropyl-cyclodextrin, 2-hydroxypropyl -β - cyclodextrin and sulfobutyl ether 7 β- cyclodextrin.

[0039] 在本发明的另一实施方案中,涂层制剂包括至少一种非水溶剂,如乙醇、异丙醇、甲醇、丙醇、丁醇、丙二醇、二甲基亚砜、甘油、N,N- 二甲基甲酰胺和聚乙二醇400。 [0039] In another embodiment of the present invention, the coating formulations include at least one non-aqueous solvent, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethylsulfoxide, glycerol, N , N- dimethylformamide and polyethylene glycol 400.

[0040] 优选地,涂层制剂具有小于约500厘泊且大于3厘泊的粘度。 [0040] Preferably, the coating formulation has less than about 500 centipoise and greater than 3 centipoise viscosity.

[0041] 在本发明的一个实施方案中,生物相容性涂层的厚度小于25微米,更优选小于10微米。 [0041] In one embodiment of the present invention, the thickness of the biocompatible coating is less than 25 microns, more preferably less than 10 microns.

[0042] 本发明还包括经皮递送装置,其具有至少一个涂覆了所述制剂的微突出物,其配置为可以穿透角质层。 [0042] The present invention further comprises a transdermal delivery device having at least one of the coated microprojection formulation, which can be configured to penetrate the stratum corneum.

[0043] 在本发明的一个实施方案中,所述装置具有至少约10个微突出物/cm2,更优选至少约200-2000个微突出物/cm2的微突出物密度。 [0043] In one embodiment of the invention, the device having at least about 10 microprojections / cm2, the microprojection density is more preferably at least about 200-2000 microprojections / cm2. [0044] 在一个实施方案中,由不锈钢、钛、镍钛合金或者相似的生物相容性材料制造所述微突出物。 [0044] In one embodiment, made of stainless steel, titanium, nickel-titanium alloys or similar biocompatible material for producing the microprojections.

[0045] 在另一实施方案中,由非传导性材料,如聚合物制造微突出物。 [0045] In another embodiment, a non-conductive material, such as a polymer manufactured microprojections. 备选地,可以将微突出物用非传导性材料,如Parylene®、或者疏水材料,如Teflon®、硅或者其他低能量材料涂覆。 Alternatively, the micro-projections with a non-conductive material, such as Parylene®, or a hydrophobic material, such as Teflon®, silicon or other low energy material coating.

[0046] 通常,本发明的方法包括对经皮递送装置应用生物活性剂的涂层,其中经皮递送装置包含许多角质层穿刺性微突出物,所述方法包括如下步骤:提供生物活性剂制剂,通过加入不挥发性平衡离子稳定制剂,和对微突出物应用所述制剂。 [0046] Generally, the method of the present invention comprises a coating means for application of a biologically active agent transdermal delivery, transdermal delivery device which comprises a plurality of stratum corneum piercing microprojections, said method comprising the steps of: providing a biological active agent formulation , by addition of a non-volatile counterion stable formulation, the formulation and application of the microprojections. 优选地,以中和生物活性剂上的电荷的量加入平衡离子。 Preferably, the amount of charge on the bioactive agent is added and the counterion. 可以使用本发明的算法确定所述试剂的电荷。 It can be determined using the algorithm of the present invention, the charge of the agent.

[0047] 附图简述 [0047] BRIEF DESCRIPTION

[0048] 将参考在附图中阐明的优选实施方案更详细地描述本发明,其中: [0048] The present invention is set forth with reference to preferred embodiments described in more detail in the accompanying drawings, in which:

[0049] 图1显示了作为pH函数的乙酸(pKa 4.75)的电荷特征的图; [0049] FIG. 1 shows a diagram of the charge characteristics as a function of pH acetic acid (pKa 4.75); and

[0050] 图2显示了作为pH函数的不带电乙酸和带电的乙酸盐离子的摩尔比的图; [0050] FIG. 2 shows the molar ratios as a function of pH FIG uncharged acetic acid and acetates charged ions;

[0051] 图3显示了作为pH函数的芬太尼的电荷特征的图。 [0051] FIG. 3 shows a diagram of fentanyl charge characteristics as a function of pH.

[0052] 图4显示了作为pH函数的中性(芬太尼碱)和带电的(芬太尼+1)芬太尼种类的摩尔比的图; [0052] FIG. 4 shows a function as a neutral pH (fentanyl base) and a charging molar ratio (fentanyl + 1) of fentanyl FIG species;

[0053] 图5显示了作为pH函数的hPTH(l_34)的电荷特征的图; [0053] FIG. 5 shows the charge characteristics hPTH (l_34) as a function of pH;

[0054] 图6显示了作为pH函数的hPTH(l_34)的净电荷种类的摩尔比的图; [0054] Figure 6 shows as a function of hPTH pH (l_34) molar ratio of the net charge of the type of Figure 1;

[0055] 图7显示了作为pH函数的乙酸芬太尼、乙酸和芬太尼中性形式(芬太尼碱)的摩尔比的图; [0055] Figure 7 shows a fentanyl acid, acetic acid and the molar ratio of the neutral form of fentanyl (fentanyl base) as a function of pH FIG;

[0056] 图8显示了作为pH函数的乙酸和hPTH(l_34)的净中性形式的摩尔比的图; [0056] Figure 8 shows as a function of acid and hPTH pH (l_34) molar ratio in FIG net neutral form;

[0057] 图9显示了包含hGRF类似物的肽的电荷特征的图; [0057] FIG. 9 shows charge characteristics of the hGRF analog comprising peptide;

[0058] 图10是显示挥发性平衡离子从涂层的外层丧失的图解; [0058] FIG. 10 is a illustration of a volatile counterion loss from the outer layer coating;

[0059] 图11是将结合本发明使用的微突出物阵列的透视图; [0059] FIG. 11 is a perspective view of the binding of the microprojection array of the present invention;

[0060] 图12是微突出物阵列的透视图,其显示了已经涂覆的若干微突出物。 [0060] FIG. 12 is a perspective view of a microprojection array thereof, which shows several of the microprojections have been coated.

[0061] 发明详述 [0061] DETAILED DESCRIPTION

[0062] 定义 [0062] defined

[0063] 除非另外指出,本文所用的下面的术语具有下面的含义。 [0063] Unless otherwise indicated, the following terms used herein have the following meanings.

[0064] 术语“经皮”指为了局部或者全身性治疗,将试剂递送到皮肤里面和/或穿过皮肤递送。 [0064] The term "transdermal" refers to the local or systemic treatment, the delivery of agent to the skin inside and / or delivery through the skin.

[0065] 术语“经皮通量”指经皮递送速率。 [0065] The term "transdermal flux" means the rate of transdermal delivery.

[0066] 文中所用术语“共同递送”指在试剂递送之前、试剂经皮通量之前和期间、试剂经皮通量期间,试剂经皮通量期间和之后,和/或试剂经皮通量之后经皮施用补充试剂。 After [0066] As used herein, the term "co-delivery" means delivery of the agent prior to, the transdermal agent flux before and during, during transdermal agent flux during transdermal agent flux and after, and / or the agent transdermal flux transdermal administration of supplementary reagents. 此夕卜,两种或者更多种试剂可以涂覆到微突出物上,导致试剂的共同递送。 This evening Bu, two or more agents may be coated onto the microprojections resulting in co-delivery agent.

[0067] 文中所用术语“生物活性剂”或者“活性剂”指含有药物的物质组合物或者混合物,其当以治疗有效量施用时是药理学有效的。 [0067] As used herein, the term "biologically active agent" or "active agent" refers to a pharmaceutical composition of matter or mixture, which when administered in a therapeutically effective amount as is pharmacologically effective.

[0068] 此类试剂包括所有主要治疗领域的治疗剂,包括,但不限于:抗感染药,如抗生素和抗病毒剂;镇痛药,包括芬太尼、舒芬太尼、雷米芬太尼、丁丙诺啡和镇痛药组合;麻醉剂;厌食剂;抗关节炎药;止喘药,如特布他林;抗惊厥剂;抗抑郁药;抗糖尿病剂;止泻药;抗组胺药;消炎药;抗偏头痛制剂;抗运动病制剂,如东茛菪碱和奥丹西隆;止恶心药;抗瘤剂;抗帕金森综合征药物;止痒剂;抗精神病药;退热药;镇痉剂,包括胃肠和泌尿镇痉剂;抗胆碱能药;拟交感神经药;黄嘌呤衍生物;心血管制剂,包括钙通道阻断剂,如硝苯地平;β -阻断剂;β激动剂,如多巴酚丁胺和利托君;抗心律不齐剂;抗高血压药,如阿替洛尔;ACE抑制剂,如雷尼替丁;利尿剂;血管舒张剂,包括全身、冠状、外周和脑血管舒张剂冲枢神经系统刺激剂;咳嗽 [0068] Such agents include therapeutic agents in all the major therapeutic areas including, but not limited to: anti-infectives such as antibiotics and antiviral agents; analgesics, including fentanyl, sufentanil, too Lei Mifen Nepal, buprenorphine and analgesic combinations; anesthetics; anorectic agents; antiarthritics; antiasthmatics such as terbutaline; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines drugs; anti-inflammatory agents; anti-migraine preparations; anti-motion sickness preparations such as scopolamine and ondansetron; antinauseants; antineoplastic agents; anti-parkinsonism drugs; antipruritic agents; antipsychotics; retire hot medicine; antispasmodics, including gastrointestinal and urinary antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers such as nifedipine; β - blockers; beta] agonists, such as dobutamine and ritodrine; antiarrhythmic agents; antihypertensives, such as atenolol; the ACE inhibitors such as ranitidine; diuretics; vascular vasodilators, including systemic, coronary, peripheral and cerebral vasodilators, central nervous system stimulants punch; cough 感冒制剂;减充血剂;诊断剂;激素,如甲状旁腺激素;安眠药;免疫抑制剂;肌肉松驰剂;抗副交感神经药;拟副交感神经药;如列腺素;蛋白质;妝;精神兴奋剂;镇静药;和安定剂。 Cold preparations; decongestants; diagnostic agents; hormones, such as parathyroid hormone; hypnotics; immunosuppressant; muscle relaxants; parasympatholytics; parasympathomimetics; as prostaglandins; proteins; makeup; psychostimulant agent; sedatives; and tranquilizers. 其他适宜的试剂包括血管收缩剂、抗愈合剂和途径开放调节剂。 Other suitable agents include vasoconstrictors, anti-healing agents and pathway patency modulators.

[0069] 试剂的其他特定实例包括,但不限于,生长激素释放激素(GHRH)、生长激素释放因子(GHRF)、胰岛素、insultropin、降钙素、奥曲肽、内啡肽、TRN、NT_36(化学名称:N-[[ (s)-4-氧代-2-氮杂环丁基]羰基]-L-组氨酰-L-脯氨酰胺)、Iiprecin、垂体激素(例如,HGH、HMG、醋酸去氨加压素,等等)、卵泡类黄体素、aANF、生长因子,如生长因子释放因子(GFRF)、bMSH、GH、促生长素抑制素、缓激肽、促生长素、血小板衍生生长因子释放因子、天冬酰胺酶、硫酸博来霉素、木瓜凝乳蛋白酶、缩胆囊素、绒毛膜促性腺激素、促红细胞生成素、依前列醇(血小板聚集抑制剂)、胰高血糖素、HCG、水蛭肽、透明质酸酶、干扰素α、干扰素β、干扰素Y、白细胞介素、白细胞介素-10 (IL-10)、促红细胞生成素(EPO)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、粒细胞集落刺激因子(G-CSF)、胰高血糖素、促黄 [0069] Specific examples of other agents include, but are not limited to, growth hormone releasing hormone (GHRH), growth hormone releasing factor (GHRF), insulin, insultropin, calcitonin, octreotide, endorphin, TRN, NT_36 (chemical name : N - [[(s) -4- oxo-2-azetidinyl] carbonyl] -L- histidyl -L-prolinamide), Iiprecin, pituitary hormones (e.g., HGH, HMG, acetate desmopressin, etc.), follicle-based progesterone, AANF, growth factors, such as growth factor releasing factor (GFRF), bMSH, GH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor releasing factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, HCG, hirulog, hyaluronidase, interferon [alpha], interferon beta], interferon Y, interleukin, interleukin -10 (IL-10), erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), glucagon, luteinizing 体生成激素释放激素(LHRH)、LHRH类似物(如性瑞林、醋酸亮丙瑞林、布噻来灵、曲普瑞林、高那瑞林和napfarelin、促卵泡激素(尿促卵泡素(FSH)和LH))、催产素、链激酶、组织纤溶酶原激活物、尿激酶、血管加压素、脱氨基[Val4,D-ArgS]精氨酸血管加压素、去氨加压素、促肾上腺皮质激素(ACTH)、ACTH类似物,如ACTH(l-24)、ANP、ANP清除抑制剂、血管紧张肽II拮抗齐IJ、抗利尿激素激动剂、缓激肽拮抗剂、ceredase, CST、降钙素基因相关肽(CGRP)、脑啡肽、FAB片段、IgE肽抑制因子、IGF-1、神经营养因子、集落刺激因子、甲状旁腺激素和激动剂、甲状旁腺激素拮抗剂、甲状旁腺激素(PTH) ,PTH类似物,如ΡΤΗ(1-34)、前列腺素拮抗剂、喷替替特、C蛋白、S蛋白、肾素抑制剂、胸腺素α -1、溶栓剂、TNF、血管加压素拮抗剂类似物、α -1抗胰蛋白酶(重组的)和TGF-β。 Generating body hormone-releasing hormone (LHRH), LHRH analogs (such as goserelin, leuprolide, thiophene cloth to Ling, triptorelin, gonadorelin high and napfarelin, follicle stimulating hormone (FSH urinary hormone (FSH) and LH)), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, deamination [Val4, D-argS] arginine vasopressin, desmopressin, adrenocorticotropic hormone (ACTH), ACTH analogs such as ACTH (l-24), ANP, ANP clearance inhibitors, angiotensin II antagonist together IJ, antidiuretic hormone agonists, bradykinin antagonists, ceredase, CST calcitonin gene-related peptide (of CGRP), enkephalins, FAB fragments, IgE peptide inhibitors, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, parathyroid hormone (PTH), PTH analogs, such as ΡΤΗ (1-34), prostaglandin antagonists, for Laid pentetate, C protein, S protein, renin inhibitors, thymosin α -1, thrombolytic agent , TNF, vasopressin antagonist analogs, α -1-antitrypsin (recombinant), and TGF-β.

[0070] 文中所用术语“生物活性剂”或“活性剂”还指物质组合物或者混合物,其含有疫苗或者其他免疫活性剂或者能够引发产生免疫活性剂、并且当以免疫学有效量施用时是直接或者间接免疫学有效的试剂。 [0070] As used herein, the term "biologically active agent" or "active agent" also refers to a composition of matter or mixture containing a vaccine or other immunologically active agent or capable of eliciting an immune active agent, and, when administered in an immunologically effective amount is a direct or indirectly immunologically effective agent.

[0071] 适宜的疫苗包括病毒和细菌、基于蛋白质的疫苗、基于多糖的疫苗、基于核酸的疫苗和其他抗原剂。 [0071] Suitable vaccines include viruses and bacteria, protein-based vaccines, polysaccharide-based vaccine, and a vaccine based on nucleic acids of other antigens. 适宜的抗原剂包括,但不限于,蛋白质、多糖缀合物、寡糖和脂蛋白形式的抗原。 Suitable antigenic agents include, but are not limited to, proteins, polysaccharide conjugates, oligosaccharides, and lipoproteins in the form of an antigen. 这些亚基疫苗包括百日咳博德特氏菌(重组的PT accince-无细胞的)、破伤风梭菌(纯化的,重组的)、白喉棒杆菌(纯化的,重组的)、巨细胞病毒(糖蛋白亚基)、A组链球菌(糖蛋白亚基、糖缀合物A组多糖与破伤风类毒素,M蛋白质/肽连接到毒性亚基载体,M蛋白质,多价型特异的表位,半胱氨酸蛋白酶,C5a肽酶)、乙型肝炎病毒(重组Pre S1、Pre-S2、S、重组核心蛋白质)、丙型肝炎病毒(重组表达的表面蛋白质和表位)、人乳头瘤病毒(衣壳蛋白,TA-GN重组蛋白质L2和E7[来自HPV-6]、来自HPV-1l的MED1-501重组VLPL1、四价重组BLP LI [来自HPV-6]、HPV-11、HPV-16 和HPV-18、LAMP-E7[来自HPV-16])、侵肺军团菌(纯化的细菌表面蛋白质)、脑膜炎萘瑟氏球菌(与破伤风类毒素的糖缀合物)、铜绿假单胞菌(合成肽)、风疹病毒(合成肽)、肺炎链球菌(缀合脑膜炎球菌B OMP的糖缀合物[1、4、5、68、9114、18(:、1 These subunit vaccines include Bordetella pertussis (PT accince- recombinant acellular), Clostridium tetani (purified, recombinant), Corynebacterium diphtheriae (purified, recombinant), Cytomegalovirus (sugar subunit), group a streptococcus (glycoprotein subunit, glycoconjugate group a polysaccharide with tetanus toxoid, M protein / peptides coupled to a carrier toxic subunit, M protein, multivalent type-specific epitopes, and cysteine ​​protease, of C5a peptidase), hepatitis B virus (recombinant Pre S1, Pre-S2, S, recombinant core protein), hepatitis C virus (recombinant surface protein expressed epitopes), human papilloma virus (capsid protein, TA-GN recombinant protein L2 and E7 [from HPV-6], MED1-501 VLPL1 from recombinant HPV-1l tetravalent recombinant BLP LI [from HPV-6], HPV-11, HPV-16 and HPV-18, LAMP-E7 [from HPV-16]), Legionella pneumophila (purified bacterial surface protein), meningitis naphthalene Joseph meningitidis (tetanus toxoid glycoconjugate), Pseudomonas aeruginosa mobilis (synthetic peptides), rubella virus (synthetic peptide), Streptococcus pneumoniae (conjugated to meningococcal B OMP glycoconjugates [1,4,5,68,9114,18 (:, 1 叭、23卩]、缀合CRM197 的糖缀合物[4、6B、9V、14、18C、19F、23F]、缀合CRM1970的糖缀合物[1、4、5、6B、9V、14、18C、19F、23F]、苍白密螺旋体(表面脂蛋白)、水痘带状疱疹病毒(亚基,糖蛋白)和霍乱弧菌(缀合脂多糖)。 A pair, Jie 23], conjugation of CRM197 glycoconjugate [4,6B, 9V, 14,18C, 19F, 23F], conjugated to CRM1970 glycoconjugates [1,4,5,6B, 9V, 14 , 18C, 19F, 23F], Treponema pallidum (surface lipoproteins), varicella zoster virus (subunit, glycoproteins), and Vibrio cholerae (conjugate lipopolysaccharide together).

[0072] 完整病毒或细菌包括,但不限于,弱化或者杀死的病毒,如巨细胞病毒、乙型肝炎病毒、丙型肝炎病毒、人乳头瘤病毒、风疹病毒和水痘带状疱疹病毒,弱化或杀灭的细菌,如百日咳博德特氏菌、破伤风梭菌、白喉棒杆菌、A组链球菌、侵肺军团菌、脑膜炎萘瑟氏球菌、铜绿假单胞菌、肺炎链球菌、苍白密螺旋体和霍乱弧菌,和它们的混合物。 [0072] The whole virus or bacteria include, without limitation, weakened or killed viruses such as cytomegalovirus, hepatitis B virus, hepatitis C virus, human papillomavirus, rubella virus, and varicella zoster virus, weakening or killed bacteria such as Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheriae, a group streptococcus, Legionella pneumophila, meningitis naphthyl Joseph meningitidis, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Treponema pallidum, Vibrio cholerae, and mixtures thereof.

[0073] 额外的通过商业途径可得到的含有抗原剂的疫苗包括,但不限于,流感疫苗、莱姆病疫苗、狂犬病疫苗、麻疹疫苗、腮腺炎疫苗、禽痘疫苗、天花疫苗、肝炎疫苗、百日咳疫苗和白喉疫苗。 [0073] Additional vaccine containing the antigen agent commercially available include, but are not limited to, flu vaccines, Lyme disease vaccine, rabies vaccine, measles vaccine, mumps vaccine, a fowl pox vaccine, smallpox vaccine, hepatitis vaccine, pertussis vaccine and diphtheria vaccine.

[0074] 包含核酸的疫苗包括,但不限于,单链和双链核酸,如超螺旋的质粒DNA ;线性质粒DNA ;粘粒;细菌人工染色体(BAC);酵母人工染色体(YAC);哺乳动物人工染色体JPRNA分子,如mRNA。 [0074] Vaccines comprising nucleic acids include, but are not limited to, single and double stranded nucleic acids, supercoiled plasmid DNA; linear plasmid DNA; cosmids; bacterial artificial chromosome (the BAC); yeast artificial chromosomes (YACs); mammal artificial chromosome JPRNA molecules, such as mRNA. 核酸的大小可以最长达数千碱基。 The size of the nucleic acid can be up to several kilobases. 此外,在本发明的某些实施方案中,核酸可以与蛋白剂偶联或者可以包括一种或多种化学修饰,如硫代磷酸酯部分。 Further, in certain embodiments of the invention, the nucleic acid can be conjugated to the protein or agent may include one or more chemical modifications, such as phosphorothioate moieties. 核酸的编码序列包含抗原序列,希望针对所述抗原产生免疫应答。 The coding sequence of a nucleic acid sequence comprising an antigen, an immune response against the desired antigen. 此外,对于DNA,启动子和多腺苷酸化序列也整合到疫苗构建体中。 Further, respect to DNA, promoter and polyadenylation sequences are also incorporated into the vaccine construct. 可以编码的抗原包括传染病的所有抗原性成分、病原体以及癌抗原。 May encode antigens include all antigenic components of infectious pathogens and cancer antigens. 从而,所述核酸可以应用于例如,传染病、癌症、变态反应、自身免疫病和炎性疾病领域。 Thus, the nucleic acid may be applied, for example, cancer, allergy, autoimmune disease, inflammatory disease and infectious disease.

[0075] 与疫苗抗原一起可以组成疫苗的适宜的免疫应答增强性佐剂包括磷酸铝凝胶;氢氧化招;藻类葡聚糖:b-葡聚糖;霍乱毒素B亚基;平均值为x = 8和y = 205的CRL1005:ABA嵌段聚合物;Y菊糖:线性(不分枝的)β-D(2-> I)聚呋喃果糖氧基-aD-葡萄糖;Gerbu佐剂:N_乙酰葡糖胺-(bl_4)-N-乙酰胞壁酰-L-丙氨酰-D-谷氨酰胺(GMDP)、二甲基二(十八烷基)氯化铵(DDA)、L-脯氨酸锌盐络合物(Ζη_Ρι.0-8)、咪喹莫特(1-(2-甲基丙基)-1Η-咪唑并[4,5-c]喹啉-4-胺;ImmTherO=N-乙酰葡糖胺基-N-乙酰胞壁酰-L-Ala-D-1soGlu-L-Ala-甘油二棕榈酸酯;MTP_PE脂质体:C59H108N6019PNa-3H20 (MTP) ;Murametide:Nac-Mur-L-AIa-D-GIn-0CH3 ;Pleuran:b_ 葡聚糖;QS-21 ;S-28463:4-氨基_a,a-二甲基-1H-咪唑并[4,5_c]喹啉-卜乙醇;sclavo 肽:VQGEESNDK.HCl (iL-1b 163-171 肽);和苏氨酰-MDP(Termurtide0):N-乙酰胞壁酰-L-苏氨酰-D-异谷氨酰胺,和白细胞介素18、IL-2、IL- [0075] Suitable adjuvants to enhance immune responses and may together form a vaccine antigen vaccine include aluminum phosphate gel; hydroxide strokes; algal glucan: b- glucan; cholera toxin B subunit; average value of x = 8 and y = 205 to CRL1005: ABA block polymer; the Y inulin: linear (unbranched) β-D (2-> I) poly-fructopyranose group -aD- glucose; Gerbu adjuvant: N _ acetylglucosamine - (bl_4) -N- acetyl-muramyl-alanyl -D- -L- glutamine (GMDP), dimethyl (octadecyl) ammonium chloride (DDA), L - proline zinc complex (Ζη_Ρι.0-8), imiquimod (1- (2-methylpropyl) -1Η- imidazo [4,5-c] quinolin-4-amine ; ImmTherO = N- -N- acetylglucosaminyltransferase acetyl muramyl -L-Ala-D-1soGlu-L-Ala- glycerol dipalmitate; MTP_PE liposomes: C59H108N6019PNa-3H20 (MTP); Murametide: Nac-Mur-L-AIa-D-GIn-0CH3; Pleuran: b_ glucan; QS-21; S-28463: 4- amino _a, a- dimethyl -1H- imidazo [4,5_c] quinoline - Bu ethanol; Sclavo peptide: VQGEESNDK.HCl (iL-1b 163-171 peptide); and threonyl -MDP (Termurtide0): N- acetyl muramyl-threonyl -D- -L- glutamyl iso amides, and interleukin-18, IL-2, IL- 12、IL-15,佐剂还包括DNA寡核苷酸,如含有CpG的寡核苷酸。此外,还可以使用编码免疫调节性淋巴因子的核酸序列,所述免疫调节性淋巴因子为例如IL-18、IL-2、IL-12、IL-15、IL_4、1L-10、Y干扰素和NK κ B调节信号传导蛋白质。 12, IL-15, Adjuvants also include DNA oligonucleotides, such as CpG containing oligonucleotides. In addition, use may also be nucleic acid sequences encoding immunomodulatory lymphokines, said immunomodulatory lymphokines, for example, IL -18, IL-2, IL-12, IL-15, IL_4,1L-10, Y-interferon and adjusting NK κ B signaling proteins.

[0076] 应该理解一种以上的试剂可以掺入到本发明方法中的试剂制剂中,并且术语“活性剂”的使用绝不排除使用两种或更多种此类试剂或药物。 [0076] It should be understood that more than one agent may be incorporated into the process of the present invention is a reagent formulation, and use of the term "active agent" in no way excludes the use of two or more such agents or drugs. 试剂可以为多种形式,如游离碱、酸、带电或不带电分子、分子络合物的组分或者非刺激性、药学上可接受的盐。 Agents can be in various forms, such as free bases, acids, charged or uncharged molecules, components of molecular complexes or nonirritating, pharmaceutically acceptable salts thereof. 同样,可以使用在身体pH、酶等条件下容易水解的试剂的简单衍生物(如醚、酯、酰胺等)。 Similarly, the body can be used in the pH, enzymes susceptible to hydrolysis conditions of simple derivatives of the agents (such as ethers, esters, amides, etc.). [0077] 当生物活性剂是药学活性剂时,应该使用术语“生物有效量”或者“生物有效比率”,并且其表示实现所希望的治疗效果(通常有益的效果)所需的药学活性剂的量或者比率。 [0077] When the biologically active agent is a pharmaceutically active agent, should the term "biologically effective amount" or "biologically effective rate", and which represents a pharmaceutically active agent required to achieve the desired therapeutic effect (typically beneficial effect) amount or rate. 用于涂层的试剂的量将是递送治疗有效量的试剂以实现所希望的治疗结果所需的量。 The amounts of reagents used for coating will deliver a therapeutically effective amount of a reagent amount necessary to achieve the desired therapeutic result. 实践中,这将取决于所递送的具体药学活性剂、递送部位、所治疗的状况的严重性、所希望的治疗效果和将试剂从涂层递送到皮肤组织的溶解和释放动力学而有很大变化。 In practice, this will depend upon the particular pharmaceutically active agent being delivered, the site of delivery, the severity of the condition being treated, the desired therapeutic effect and delivery of the agent from the coating into the dissolution and release kinetics of skin tissue while it Big change. 定义根据本文描述的方法掺入到微突出物的和经皮递送的药学活性剂的治疗有效量的精确范围是不实际的。 The definition of the methods described herein incorporating the microprojections therapeutically active agent and pharmaceutical transdermal delivery of an effective amount of the accuracy range is not practical.

[0078] 当生物活性剂是免疫活性剂时,也可以使用术语“生物有效量”或者“生物有效比率”,并且其表示刺激或引起所希望的免疫学(通常有益)效果所需的免疫学活性剂的量或者比率。 [0078] When the biologically active agent is an immunologically active agent, can also use the term "biologically effective amount" or "biologically effective rate", and which represents a desired stimulation caused or immunological (usually beneficial) effect the desired immunological or the ratio of the amount of active agent. 用于涂层中的免疫学活性剂的量将是递送需要实现所希望的免疫学结果的试剂量所需的量。 The amount of immunologically active agent employed in the coatings will be in the amount required to deliver the amount of reagent required to achieve the desired immunological result of. 实践中,这将取决于所递送的具体免疫学活性剂、递送部位以及将试剂从涂层递送到皮肤组织的溶解和释放动力学而有很大变化。 In practice, this will depend upon the particular immunologically active agent being delivered, the site of delivery and delivery of the agent from the coating into the dissolution and release kinetics of skin tissues vary greatly.

[0079] 术语“微突出物”指穿刺元件,其适于通过角质层穿刺或者切割到活动物,尤其人的皮肤下面的表皮层,或者表皮和真皮层。 [0079] The term "microprojections" refers to piercing elements which is adapted to puncture or cut through the stratum corneum to a living animal, particularly a human skin below the epidermis layer, or epidermis and dermis. 穿刺元件不应该穿刺皮肤到导致出血的深度。 Piercing elements should not pierce the skin to a depth cause bleeding. 通常,穿刺元件具有小于500 μ m,且优选小于250 μ m的刀片长度。 Typically, the piercing element is less than 500 μ m, and preferably less than 250 μ m of the length of the blade. 微突出物通常具有约10到200 μ m的宽度和约5到50 μ m的厚度。 Microprojections typically have a width of μ m thickness of about 10 to 200 μ m and about 5-50. 微突出物可以形成不同的形状,如针、中空针、刀片、针、穿孔器和它们的组合.[0080] 文中所用的术语“微突出物阵列”指用于穿刺角质层的以阵列排列的多个微突出物。 Microprojections may be formed in different shapes, such as needles, hollow needles, blades, needle, punch, and combinations thereof. [0080] As used herein, the term "microprojection array" means for piercing the stratum corneum arranged in an array a plurality of microprojections. 通过从薄片蚀刻或者冲压许多微突出物并将所述微突出物折叠或者弯曲到薄片平面外来形成图11中所示的结构可以形成微突出物阵列。 By etching or punching from the sheet a number of micro projections and said microprojection folded or bent into the configuration shown in FIG plane of the sheet 11 may be formed foreign formed microprojection array. 还可以以其他公知的方式形成微突出物阵列,所述方法为例如Zuck的美国专利号6,050,988中公开的形成一个或多个条,其沿着每一个条的边有微突出物。 May also be formed microprojection array to other well-known manner, for example, the method of U.S. Patent No. 6,050,988 Zuck form disclosed in one or more strips, one strip along each side of the micro-projections . 微突出物阵列可以包括中空针头,其装有干燥的药学活性剂。 Microprojection array may include hollow needles which dried with pharmaceutically active agents.

[0081] 文中所用“聚电解质”指具有离子种类的生物活性剂的制剂。 [0081] As used herein, "polyelectrolyte" refers to a formulation having a biologically active agent ion species. 聚电解质是大分子物质,其当溶于水或者另一离子化溶剂中时,解离得到多电荷的阴离子或者阳离子。 Polyelectrolytes are macromolecular substance which, when dissolved in water or another ionizing solvent when the dissociation obtain multiple charged anion or cation. 例如,包含多肽的试剂经常具有复杂的离子特征,其由具有酸性和碱性官能团的多个氨基酸残基导致。 For example, the reagent comprising a polypeptide having often complex ionic character, which is caused by a plurality of amino acid residues having acidic and basic functional groups.

[0082] 挥发性平衡离子定义为至少一个pKa高于约2和具有在Patm下低于约50°C的熔点或者低于约170°C的沸点的弱酸。 [0082] The volatile counterion is defined as at least one pKa higher than about 2 and a weak acid having a boiling point lower than a melting point of about at 50 ° C at Patm or below about 170 ° C is. 此类酸的实例包括乙酸、丙酸、戊酸等等.挥发性平衡离子还定义为具有低于约12的至少一种pKa和在Patm下低于约50°C的熔点或者低于约170°C的沸点的弱碱。 Examples of such acids include acetic acid, propionic acid, valeric acid and the like. The volatile counterion is further defined as having at least one pKa of less than about less than about 12 and a melting point of 50 ° C at or below about 170 Patm weak base ° C. boiling. 此类碱的实例包括氨和吗啉。 Examples of such bases include ammonia and morpholine.

[0083] 非挥发性平衡离子定义为具有至少一个酸性pKa和在Patm下高于约50°C的熔点或者高于约170°C的沸点的弱酸。 [0083] Non-volatile counterions are defined as having at least one acidic pKa and a melting point greater than about at 50 ° C at Patm about 170 ° C or higher than the boiling point of a weak acid. 此类酸的实例包括柠檬酸、琥珀酸、羟基乙酸、葡糖酸、葡糖醛酸、乳酸、苹果酸、丙酮酸、酒石酸、羟基丙二酸和富马酸。 Examples of such acids include citric, succinic, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid and fumaric acid. 非挥发性平衡离子还定义为具有至少两个酸性PKa和至少一个碱性pKa的酸性两性离子,从而与碱性基团数目相比具有至少一个额外的酸性基团。 Non-volatile counterions are also defined as having at least two acidic zwitterionic PKa values ​​and at least one basic pKa, so that compared to the number of basic groups having at least one additional acidic group. 此类化合物的实例包括谷氨酸和天冬氨酸。 Examples of such compounds include glutamic acid and aspartic acid.

[0084] 非挥发性平衡离子还定义为具有至少一个碱性pKa和在Patm下高于约50°C的熔点或者高于约170°C的沸点的弱碱。 [0084] Non-volatile counterions are also defined as having at least one basic pKa and greater than about at 50 ° C at Patm melting point or boiling point of about 170 ° C above the weak base. 此类碱的实例包括单乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、葡甲胺(methyglucamine)、葡糖胺。 Examples of such bases include monoethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine (methyglucamine), glucosamine. 非挥发性平衡离子也可以定义为具有至少一个酸性pKa和至少两个碱性pKa的碱性两性离子,其中碱性pKa数大于酸性pKa数。 Non-volatile counterions may also be defined as having at least one acidic pKa and a basic zwitterion at least two basic pKa, wherein the acid number is greater than the basic number of pKa pKa. 此类化合物的实例包括组氨酸、赖氨酸和精氨酸。 Examples of such compounds include histidine, lysine and arginine.

[0085] 非挥发性平衡离子还定义为具有至少一个低于约2的pKa的强酸。 [0085] Non-volatile counterions are also defined as a strong acid having at least one pKa lower than about 2. 此类酸的实例包括盐酸、氢溴酸、硝酸、磺酸、硫酸、马来酸、磷酸、苯磺酸和甲磺酸。 Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid. 非挥发性平衡离子还定义为具有至少一个高于约12的pKa的强碱。 Non-volatile counterions are also defined as having at least one pKa higher than about 12. strong base. 此类碱的实例包括氢氧化钠、氢氧化钾、氢氧化钙和氢氧化镁。 Examples of such bases include sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.

[0086] 当指平衡离子的挥发性时,将总是提及平衡离子的非离子形式的挥发性(例如,乙酸对乙酸盐)。 [0086] When referring to a volatile counterion, will always be mentioned nonionic form volatile counterion (e.g., acetic acid acetate).

[0087] 某些药物具有类似强碱或者强酸(例如,季铵盐,如溴化可利啶或者甘罗溴铵,硫酸衍生物,如多硫酸戊聚糖,一些磷酸衍生物,如核酸)的表现并且在通常用于生产药物制剂的宽pH范围(即,4-10)中被完全离子化。 [0087] Certain drugs have similar strong base or a strong acid (e.g., quaternary ammonium salts, such as bromide, can benefit piperidine or glycopyrrolate, sulfuric acid derivatives, such as pentosan polysulfate, some of the phosphoric acid derivatives, nucleic acid) performance in a wide pH range and is usually used for the production of pharmaceutical preparations (i.e., 4-10) and is completely ionized. 其他化合物,如中性多糖(即,胰岛素和葡聚糖)不表现酸性或者碱性功能。 Other compounds, such as neutral polysaccharides (i.e., dextran, and insulin) do not show acidic or basic functionality. 对于这些化合物类别,水中的溶解性不明显受到pH的影响,并且本发明不适用。 For these classes of compounds, the solubility in water of not significantly affected by pH, and the present invention is not applicable.

[0088] 相反地,许多药物具有弱酸或弱碱的表现。 [0088] In contrast, many drugs have a weak acid or base performance. 它们的中性形式通常具有低水溶解性。 Their neutral form generally have a low solubility in water. 例如,许多小分子化合物,如芬太尼或者肽如hPTH(l-34)的中性形式在水中是明显不溶的。 For example, many small molecule compounds, such as fentanyl or a neutral form of such a peptide hPTH (l-34) in water insoluble apparent. 这些化合物当处于带电状态时在水中显示出最大溶解性。 These compounds, when in a charged state show maximum solubility in water. 因为它们的弱酸性或者碱性特性,所以中性和离子形式的各个浓度,以及从而在水中的溶解性是依赖PH的。 Because they are weakly acidic or basic characteristics, so that each concentration of the neutral and ionic forms, and thus the solubility in water is dependent on the PH. 本发明应用于这类药物。 The present invention is applied to such drugs. 如从下面讨论的实施例中看是显然的,该类型药物与该非挥发性平衡离子以足够最小化药物的中性形式的存在的比例组合可确保制剂中药物的水溶解性、固态储存期间的稳定性,和施用时生物学流体的溶解。 As is discussed in the following examples is clearly seen, the proportion of the pharmaceutical combination of this type of non-volatile counter ion sufficient to minimize the neutral form of the drug may be present to ensure that the water solubility of the drug in the preparation, during solid state stability, and dissolution when administered to a biological fluid.

[0089] 对片或者部件区域的参考和片或者部件的每区域的一些性质的参考指所述片的外圆周或者边界包围的区域。 [0089] Some properties of the reference region and each region of the sheet member or sheet member or the reference refers to a region of the outer circumference or border of the sheet enclosed.

[0090] 术语“模式涂覆”指将试剂涂覆到微突出物的所选区域。 [0090] The term "pattern coating" refers to a selected area of ​​a reagent coated microprojections. 一种以上的试剂可以模式涂覆到一个微突出物阵列上。 More than one agent may be pattern coated onto a microprojection array. 可以使用已知的微流体分配技术,如微量移液或者喷墨涂覆可以将模式涂层应用于微突出物。 Using known micro-fluid dispensing techniques such as micropipetting or inkjet coating may be a coating applied to the microprojection mode.

[0091] 将从本发明受益的药物含有至少一种弱酸性和/或一种弱碱性功能,并且在pH4到pHIO的pH范围内以中性种类存在。 [0091] The present invention would benefit from the drug comprises at least one weak acid and / or a weak basic function, and in the pH range pH4 to pHIO of neutral species present. 不带电种类和带电种类之间的摩尔比在该pH范围内将为至少I比100。 The molar ratio between uncharged species and charged species within this pH range for I ratio of at least 100.

[0092] 不挥发性平衡离子以足够将药物的不带电种类和带电种类之间的摩尔比减小到小于约I比100的量存在。 [0092] The non-volatile counter ion sufficient to drug molar ratio between uncharged species and charged species will be reduced to less than about 100 is present in an amount of more than I.

[0093] 本发明基于如下发现,即从掺入挥发性平衡离子的制剂制备的涂层将从该涂层的外表面丧失挥发性平衡离子。 [0093] The present invention is based on the finding that the loss of a volatile counterion is incorporated in the coating formulation is prepared from a volatile counterion from the outer surface of the coating. 这导致涂层的pH的改变并且可以增加不带电的生物活性剂的量,所述活性剂在生理学流体中溶解性较小。 This leads to changes in pH of the coating and may increase the amount of uncharged biologically active agent, said active agent is less soluble in physiological fluid.

[0094] 本发明提供了含有生物活性剂的涂层制剂,其当在一个或多个微突出物上涂覆并干燥时将形成涂层,插入到皮肤时,该涂层减小平衡离子从涂层的丧失,稳定涂层的pH和增强涂层的溶解性。 [0094] The present invention provides coating formulations comprising the biologically active agent, which when one or more microprojections coated and dried to form a coating, is inserted into the skin, the coating decreases from counterion loss of coating, pH stability and enhanced solubility of the coatings of the coating. 本发明还包括装置,其具有从该装置延伸的许多角质层穿刺性突出物。 The present invention further comprises means having a number of projecting from the stratum corneum of the lancing device extends thereof. 所述微突出物适于通过角质层穿刺到下面的表皮层,或者表皮和真皮层,但是不刺入如此之深以致于达到毛细血管床和导致明显出血。 The microprojections adapted to puncture the underlying epidermis layer, or epidermis and dermis layers through the stratum corneum, but not so deep so as to pierce reach the capillary beds and cause significant bleeding. 微突出物上具有干燥涂层,其含有生物活性齐U。 Micro-projection having a dried coating thereof, comprising a bioactive homogeneous U. 所述涂层配制成可减小、最小化和/或消除挥发性平衡离子从涂层的损失,这增强了穿刺皮肤后涂层的溶解性。 The coating may be formulated to reduce, minimize and / or eliminate the loss of a volatile counterion from the coating, which enhances the solubility of the coating after piercing the skin. 穿刺皮肤的角质层后,含有试剂的涂层被体液(细胞内液和细胞外液,如组织液)溶解并释放到皮肤中用于局部或者全身治疗。 After piercing the stratum corneum of the skin, the agent-containing coating is body fluid (intracellular fluids and extracellular fluids such as interstitial fluid) and released into the skin was dissolved for topical or systemic therapy.

[0095] 如美国专利申请公开号2002/0128599描述的,通过在微突出物上干燥制剂得到固体涂层。 [0095] As described in U.S. Patent Application Publication No. 2002/0128599 is, by the microprojection coating was dried to give a solid formulation. 所述制剂通常是水性制剂。 The formulations are typically aqueous formulations. 在干燥过程期间,主要除去所有挥发物,包括水(最终固体涂层将含有最高达约10%水)。 During the drying process, mainly to remove all volatiles, including water (final solids coating will contain up to about 10% water). 如果处于离子化和非离子化形式之间平衡的挥发性化合物存在于溶液中,那么当发生干燥过程时,仅非离子化形式从制剂中消失,并且离子化形式保留在溶液中并掺入到涂层中。 If a volatile compound in equilibrium between the ionized and non-ionized form in solution is present, then when the drying process takes place, only the non-ionized form disappears from the formulation, and the ionized form stays in solution and incorporated into coating.

[0096] 在微突出物阵列上的固体涂层中,药物通常以小于约Img/单位剂量的量存在。 [0096] a solid coating on the microprojection array, the drug is typically present in an amount of less than about Img / unit dose. 加入赋形剂和平衡离子时,固体涂层的总质量小于3mg/单位剂量。 When adding an excipient and a counter ion, the total mass of the solid coating is less than 3mg / unit dose. 阵列通常存在于粘性衬垫上,该衬垫附着到一次性聚合物固位体环。 The array is typically present in the adhesive backing, the polymer spacer is attached to the disposable retainer ring. 将该组件单独包装在小药袋或者聚合物罩中。 The components separately packaged in sachets or in a polymeric cover.

[0097] 除了所述组件,该包装还含有至少3mL体积的大气(通常惰性的)。 [0097] In addition to the assembly, the package further comprises at least 3mL volume of air (usually inert). 该大体积(与涂层相比)作为任何挥发性成分的槽起作用。 The large volume (compared to the coating) as a function slot of any volatile components. 例如,在20°C下,由于蒸汽压,存在于3mL大气的乙酸的量将为约0.15mg。 For example, at 20 ° C, due to the vapor pressure, the amount of acetic acid present in the atmosphere will be about 3mL of 0.15mg. 该量通常是将乙酸用作平衡离子时固体涂层中存在的量。 The amount of the acid is usually used as the counter ion present in the solid coating amount. 此夕卜,组件的成分,如粘合剂可能作为挥发性成分的额外的槽。 This component Bu Xi, components, such as a volatile component of the adhesive may additional groove. 结果,在长期储存期间,可能涂层中存在的挥发性成分的浓度将显著改变。 As a result, during long-term storage, the concentration of volatile components may be present in the coating will be significantly changed.

[0098] 上面的条件不是药物化合物的典型的常规包装,在典型常规包装中通常存在大量赋形剂。 [0098] A typical conventional package above conditions are not pharmaceutical compound, typically present in a typical conventional excipients large package. 即使使用冻干用于注射的非常有效的生物技术化合物,在干饼中也存在非常大量过量的缓冲剂和赋形剂。 Even if very efficient lyophilized for injection of a compound of biotechnology, there is a very large excess of buffer and excipients in the dry cake. 从而,一种或多种挥发性平衡离子的丧失的效果不影响这些常规剂型的溶解。 Thus, the effect of the loss of one or more volatile counterion does not affect the dissolution of these conventional dosage forms.

[0099] 对于在所希望的pH具有阳性电荷的目的药物,平衡离子是酸。 [0099] For the purposes of the drug having a positive charge at the desired pH, counter ion is an acid. 在优选实施方案中,酸性平衡离子是非挥发性弱酸。 In a preferred embodiment, the acidic counterion is non-volatile weak acid. 在另一优选实施方案中,平衡离子是非挥发性强酸。 In another preferred embodiment, the non-volatile counterion is a strong acid.

[0100] 另一优选实施方案涉及平衡离子的混合物,其中至少一种平衡离子是强酸,并且至少一种平衡离子是非挥发性弱酸。 [0100] Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion is a strong acid and at least one non-volatile weak acid counterion.

[0101] 另一优选实施方案涉及平衡离子的混合物,其中至少一种平衡离子非挥发性酸,并且至少一种平衡离子是具有高挥发性的弱酸。 [0101] Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion non-volatile acid and at least one counterion is a weak acid with high volatility.

[0102] 酸性平衡离子以在制剂的pH下中和药物上存在的正电荷所必需的量存在。 [0102] Acidic ion balance and the amount of positive charge present on the drug at the pH of the formulation in the presence of necessary. 为了控制PH和提供足够缓冲能力,可以向药物加入过量平衡离子(作为游离酸或者盐)。 In order to control and provide adequate buffering capacity PH, excess counterion (as the free acid or salt) may be added to the drug.

[0103] 对于在所希望的pH带负电荷的目的药物,平衡离子是碱。 [0103] For negatively charged in the drug of the desired pH, the counterion is an alkali.

[0104] 在优选实施方案中,碱性平衡离子是具有低挥发性的弱碱。 [0104] In a preferred embodiment, the basic counterion is a weak base with low volatility.

[0105] 在另一优选实施方案中,平衡离子是强碱。 [0105] In another preferred embodiment, the counterion is a strong base.

[0106] 另一优选实施方案涉及平衡离子的混合物,其中至少一种平衡离子是强碱,并且至少一种平衡离子是具有低挥发性的弱碱。 [0106] Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion is a strong base and at least one counterion is a weak base with low volatility.

[0107] 另一优选实施方案涉及平衡离子混合物,其中至少一种平衡离子非挥发性碱,并且至少一种平衡离子是具有高挥发性的弱碱。 [0107] Another preferred embodiment relates to a mixture of counterions wherein at least one non-volatile counterion base, and at least one counterion is a weak base with high volatility.

[0108] 碱性平衡离子以在制剂的pH下中和目的药物上存在的负电荷所必需的量存在。 [0108] in an amount of alkali ion balance the negative charge present on the drug of interest and the pH of the formulation at present necessary. 为了控制PH和提供足够缓冲能力,可以向药物加入过量平衡离子(作为游离碱或者盐)。 In order to control and provide adequate buffering capacity PH, may be added to an excess of the drug counter ion (as the free base or salt).

[0109] 本发明涉及药物剂型,其是应用于微突出物阵列上的一个或多个微突出物的固体涂层。 [0109] The present invention relates to a pharmaceutical dosage form, which is applied on a microprojection array or a plurality of solid coating microprojections. 涂层含有离子化药物,其具有至少一种弱和/或一种碱性官能团。 Coating containing an ionic medicine, which has at least a weak and / or a basic functional group.

[0110] 含有活性剂的涂层溶解和释放的动力学将取决于许多因素,包括药物的性质、涂覆方法、涂层厚度和涂层组成(例如,涂层制剂添加剂的存在)。 [0110] The kinetics of the coating dissolution and release containing an active agent will depend on many factors, including the nature of the drug, the coating process, the coating thickness and the coating composition (e.g., the presence of coating formulation additives). 取决于释放动力学特征,必需保持经涂覆的微突出物与皮肤长时间(例如,最长达约8小时)的穿刺联系。 Depending on the release kinetics, it is necessary to maintain contact piercing microprojections coated with the skin for a long time (e.g., up to about 8 hours). 这可以通过使用粘合剂将递送装置锚定到皮肤来实现,或者通过使用如WO 97/48440中描述的锚定的微突出物来实现,将所述文献完整引用作为参考。 This may be accomplished using an adhesive anchor delivery device to the skin is achieved, or by using anchored microprojections, such as described in WO 97/48440, the complete document incorporated by reference.

[0111] 图11描绘了用于本发明的角质层穿刺微突出物经皮递送装置的一个实施方案。 [0111] FIG. 11 illustrates the present invention for stratum corneum piercing microprojection transdermal delivery device according to one embodiment. 图11显示了具有多个微突出物10的装置的一部分。 11 shows a part of a device having a plurality of microprojections 10. 微突出物10以基本上90°角从具有开口14的片12延伸。 Microprojections 10 extend at substantially a 90 ° angle from a sheet 14 having an opening 12. 片12可以掺入包括片12的衬垫的递送贴剂中,并且可以还包括用于将贴剂粘附到皮肤的粘合剂。 Sheet 12 may be incorporated into the delivery patches comprising sheet 12 of the pad, and may further include means for adhering the patch to the skin of the adhesive. 在该实施方案中,通过从薄金属片12蚀刻或者冲压许多微突出物10并将微突出物10弯折出所述片的平面可以形成微突出物。 In this embodiment, a plurality of microprojections from a plane passing through the projections 10 and the thin metal sheet 12 is etched or stamped microprojections bent out of the sheet 10 may be formed microprojection. 优选诸如不锈钢和钛的金属。 Preferred metals such as stainless steel and titanium. 金属微突出物公开在Trautman等人的美国专利6,083, 196 ;Zuck的美国专利6,050, 988 ;和Daddona等人的美国专利6,091, 975,将所述专利的公开并入本文作为参考。 Metal microprojection are disclosed in Trautman et al, U.S. Patent No. 6,083, 196; U.S. Patent No. 6,050 Zuck, and 988; Daddona et al., And U.S. Patent No. 6,091, 975, the disclosure of which is incorporated herein Reference. 通过用硅芯片蚀刻技术或者通过使用蚀刻的微模对塑料成型来形成可以用于本发明的其他微突出物。 By using silicon etching techniques or by molding plastic to form other micro-projections it can be used in the present invention using micro-etched die. 硅和塑料微突出物公开在Godshall等人,美国专利5,879,326,将其公开内容完整引用作为本文的参考。 Silicon and plastic microprojection are disclosed in Godshall et al, U.S. Patent No. 5,879, 326, the complete disclosure of which is incorporated herein by reference cited.

[0112] 图12阐明了具有微突出物10的微突出物经皮递送装置,其具有含有生物活性剂的涂层16。 [0112] FIG. 12 illustrates a delivery device 10 having microprojections of a microprojection transdermal, having a coating 16 containing a biologically active agent. 涂层16可以部分或完全覆盖微突出物10。 Coating 16 may partially or completely cover the microprojections 10. 例如,涂层可以是微突出物上的干燥模式涂层。 For example, the coating may be dried micro-projection pattern on the coating composition. 可以在形成微突出物之前或之后应用涂层。 Coating may be applied before or after the microprojections are formed.

[0113] 可以通过多种已知方法形成微突出物上的涂层。 [0113] can form a coating on the microprojections by various known methods. 一种此类方法是浸涂。 One such method is dip-coating. 浸涂可以描述为通过将微突出物部分或完全浸入到含有药物的涂层溶液中来涂覆微突出物。 By dip-coating can be described as the microprojection partially or completely immersed in the coating solution containing the medicament coated microprojections. 备选地,可以将整个装置浸入涂层溶液中。 Alternatively, the entire device can be immersed in the coating solution. 优选仅涂覆穿刺皮肤的微突出物的那些部分。 Preferably only those parts of the coated skin piercing microprojections.

[0114] 通过使用上述部分浸溃技术,可能将涂层限制于仅微突出物的顶端。 [0114] By using the partial dipping techniques, the coating may be limited to only the microprojection tip. 也有辊涂机制,其将涂层限制于微突出物的顶端。 There are also roller coating mechanism that limits the coating to the microprojection tip. 该技术描述于2002年3月15日提交的美国专利申请序号10/099,604,将其完整引用作为本文的参考。 This technique is described in US Patent Application Serial No. 15 March 2002 10 / 099,604, which is fully incorporated herein by reference.

[0115] 其他涂覆方法包括将涂层溶液喷雾到微突出物上。 [0115] Other coating methods include spraying the coating solution to microprojection. 喷雾可以包括形成涂层组合物的气溶胶悬浮液。 Spraying the coating composition may include forming an aerosol suspension. 在优选实施方案中,将形成约10到200皮升的液滴大小的气溶胶悬浮液喷雾到微突出物然后干燥。 In a preferred embodiment, an aerosol suspension forming a spray from about 10 to 200 picoliters to droplet size microprojections and then dried. 在另一实施方案中,非常小量的涂层溶液可以作为模式涂层18沉积在微突出物上。 In another embodiment, a very small amount of the coating solution as a pattern coating 18 can be deposited on the microprojections. 可以使用用于将沉积的液体定位在微突出物表面的分配系统应用模式涂层18。 It may be used for positioning the deposited liquid on the surface of the micro-protrusion pattern coating application of the dispensing system 18. 沉积的液体的量优选为0.5到20nl/微突出物。 The amount of the deposited liquid is preferably 0.5 to 20nl / microprojections. 适宜的精确定量的液体分配器的实例公开在美国专利5,916,524,5, 743,960,5, 741,554和5,738,728,将它们的公开内容完整引用作为本文参考。 Examples of suitable precision quantitative liquid dispenser is disclosed in U.S. Patent No. 5,916,524,5, 743,960,5, 741,554 and 5,738,728, the complete disclosures of which are incorporated herein by reference. 使用喷墨技术,用已知的电磁阀分配器,任选使用通常使用电场控制的流体运动装置和定位装置也可以应用微突出物涂层溶液。 Using ink jet technology using known solenoid valve dispensers, optional fluid using movement means and positioning means are usually controlled using an electric field may be applied microprojection coating solution. 来自本领域已知的印刷工业或者类似的液体分配技术的其他液体分配技术也可以用于应用本发明的模式涂层。 Other liquid dispensing technology known in the art from the present printing industry or similar liquid dispensing technology may also be used in the coating mode of application of the present invention.

[0116] 在所有情况中,应用涂层后,通过多种方法使涂层溶液在微突出物上干燥。 [0116] In all cases, after application of the coating, the coating solution was dried by various methods on the microprojections. 在优选实施方案中,经涂覆的装置在环境温度下干燥。 In a preferred embodiment, the coated device was dried at ambient temperature. 然而,可以用多种温度和湿度水平将涂层溶液干燥到微突出物上。 However, various temperatures and humidity levels with the coating solution is dried onto the microprojections. 此外,可以将装置加热、冻干、冷冻干燥或者用类似技术从涂层除去水。 Further, the device can be heated, lyophilized, freeze dried or similar techniques used to remove water from the coating.

[0117] 许多因素影响化合物的挥发性。 [0117] Many factors affect the volatile compounds. 这些因素包括温度、大气压和化合物的蒸汽压。 These factors include the temperature of the vapor pressure, atmospheric pressure and compounds. 挥发过程是依赖时间的。 Volatilization process is time-dependent. 此外,离子化化合物与它们的非离子化形式相比具有低得多的挥发性。 In addition, ionic compounds compared to their non-ionized form has a much lower volatility. 例如,乙酸具有118°C的沸点,而乙酸钠基本上是不挥发的。 For example, acid having a boiling point of 118 ° C, while sodium acetate is essentially non-volatile. 如果溶液中存在处于离子化和非离子化形式平衡的挥发性化合物,那么仅非离子化形式从溶液消失并且离子化形式保留在溶液中。 If in the ionized and non-ionized form volatile compounds present balanced solution, only the non-ionized form disappears from the solution and the ionized form stays in solution.

[0118] 如果挥发性化合物是弱酸AH,那么在溶液中发生下面的平衡: [0118] If the volatile compound is a weak acid AH, then the following equilibrium occurs in solution:

[0119] [0119]

AHOA+H+ AHOA + H +

[0120] Kal为AH的平衡常数,该平衡可以写作: [0120] Kal equilibrium constant for the AH, the equilibrium can be written:

[0121] Kal = (Al X (H+)/(AH) [0121] Kal = (Al X (H +) / (AH)

[0122] Q0、(H+)和(AH)代表溶液中存在的种类的浓度。 [0122] Q0, (H +) and (AH) representative of species present in the solution concentration.

[0123] 如果AH是挥发性的,那么平衡将向A—+H+ => AH移动以满足平衡定律。 [0123] If AH is volatile, then the equilibrium would A- + H + => AH move to satisfy equilibrium. 最后,挥发性弱酸的全部物质将从溶液中消失。 Finally, all of the volatile substance from a weak acid solution disappear.

[0124] 如果挥发性化合物是弱碱(B),那么发生下面的平衡: [0124] If the volatile compound is a weak base (B), then the following equilibrium occurs:

[0125] [0125]

B+H+公BH+ B + H + well BH +

[0126] Ka2为平衡常数,该平衡可以写作: [0126] Ka2 is the equilibrium constant, the balance can be written as:

[0127] Ka2 = (B) X (H+) / (BH+) [0127] Ka2 = (B) X (H +) / (BH +)

[0128] (B)、(H+)和(BH+)代表溶液中存在的种类的浓度。 [0128] (B), (H +) and concentration (BH +) representative of species present in solution.

[0129] 如果B是挥发性的,那么平衡向BH+ => B+H+移动以满足平衡定律。 [0129] If B is volatile, then the equilibrium to BH + => B + H + moves to satisfy equilibrium. 最后挥发性弱碱的全部物质将从溶液中消失。 Finally, all the material from volatile weak base solution disappear.

[0130] 当弱酸和弱碱在溶液中混合时,根据下面的平衡,它们形成盐: [0130] When a mixed weak base and a weak acid in solution, according to the following equilibrium which form salts:

[0131] [0131]

AH+BOA*+BH+ AH + BOA * + BH +

[0132] Kal和Ka2分别代表AH和B的平衡常数,该平衡可以写作: [0132] Kal and Ka2 represent equilibrium constants AH and B, the balance can be written as:

[0133] Kal/Ka2 = QO X (BH+) / (AH) X (B)。 [0133] Kal / Ka2 = QO X (BH +) / (AH) X (B).

[0134] 如果AH是挥发性的,则平衡将向A_+BH+=>AH+B移动以满足平衡定律。 [0134] If AH is volatile, the equilibrium will A_ + BH + => AH + B move to satisfy equilibrium. 净结果将是游离碱的浓度的增加和导致PH的增加。 The net result will be an increase in the concentration of free base and leads to an increase of PH.

[0135] 相反地,如果B是挥发性的,则平衡将相同地移动,净结果是游离酸的浓度增加和PH的减小。 [0135] Conversely, if B is volatile, the equilibrium will move the same, the net result is an increase in the concentration of free acid and PH decreases. 强酸是一个特例,因为许多强酸是高度挥发性的。 Strong acid is a special case, because a lot of strong acid is highly volatile. 实际上,盐酸在环境条件下是气体。 Indeed, hydrochloric acid is a gas at ambient conditions. 当与碱结合时,它们形成不挥发性盐,因为除了某些酸的极端pH之外,它们在宽pH范围内是完全离子化的。 When combined with a base, they form non-volatile salts, extreme pH since addition of certain acids, they are in a wide pH range is fully ionized. 在溶液或者固态,在溶液和大气或者固体和大气界面发生平衡离子的挥发。 In solution or a solid, volatile counterion in solution or a solid and the atmosphere, and the atmosphere interface. 在溶液中,溶质的高扩散系数使得界面和溶液主体之间的浓度差异最小。 In solution, such that the high diffusion coefficient of the solute concentration difference between the interface and the bulk of the solution is minimized.

[0136] 相反地,在固态,扩散系数非常低或者不存在,且在界面和溶液的主体之间实现了挥发性平衡离子的更大浓度梯度。 [0136] In contrast, in the solid state, the diffusion coefficient is very low or does not exist and the interface between the body and the solution allows greater concentration gradient of the volatile counterion. 最后,涂层的外层中平衡离子耗尽,而与最初干燥状态相比固体涂层的主体相对不变(见图10)。 Finally, the outer coating is equilibrated ion depletion, compared with the initial state of the solid coating is dried body relatively unchanged (see FIG. 10). 如果平衡离子与在其中性净电荷状态基本上不溶的药物结合,那么该情形可以导致高度不溶的外部涂层。 If the counterions of which in combination with the net charge state of the drug is substantially insoluble, then the situation may result in highly insoluble outer coating. 实际上,如将在实施例1中详细解释的,平衡离子的挥发导致形成水不溶性的中性种类。 Indeed, as will be explained in detail in Example 1, volatile counterion results in the formation of water-insoluble neutral species. 这反过来又危害在暴露于生物学流体后药物从固体涂层的溶解。 This in turn was dissolved hazards upon exposure to a biological fluid drug from a solid coating.

[0137] 可以将其他已知的制剂佐剂加入到涂层溶液中,只要它们不会不利地影响涂层溶液的必要的溶解性和粘性特征和干燥涂层的物理完整性。 [0137] Other known formulation adjuvants may be added to the coating solution and the physical integrity of the necessary solubility and viscosity characteristics so long as they do not adversely affect the coating solution and drying the coating.

[0138] 通常,在本发明提到的实施方案中,平衡离子的量将中和生物活性剂的电荷。 [0138] Generally, in the noted embodiments of the invention, the amount of counter ion of the charge and the bioactive agent. 在这种实施方案中,平衡离子或者平衡离子混合物以中和在制剂的PH下存在于试剂上的电荷必需的量存在。 In such embodiments, the counterion or the mixture of counterion is present in an amount necessary for neutralization of charge present on the agent at PH formulation. 可以将过量平衡离子(作为游离酸或者盐)加入到肽中以控制PH和提供足够缓冲能力。 Excess counterion may be (as the free acid or a salt thereof) added to the peptide to provide adequate control and PH buffering capacity.

[0139] 在另一优选实施方案中,平衡离子是强酸。 [0139] In another preferred embodiment, the counterion is a strong acid. 强酸可以定义为具有至少一个低于约2的pKa。 It may be defined as at least a strong acid having a pKa less than about 2. 此类酸的实例包括盐酸、氢溴酸、硝酸、磺酸、硫酸、马来酸、磷酸、苯磺酸和甲磺酸。 Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid.

[0140] 另一优选实施方案涉及平衡离子的混合物,其中至少一种平衡离子是强酸,并且至少一种平衡离子是低挥发性弱酸。 [0140] Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion is a strong acid and at least one counterion is a low volatility weak acid.

[0141] 另一优选实施方案涉及平衡离子的混合物,其中至少一种平衡离子是强酸,并且至少一种平衡离子是高挥发性弱酸。 [0141] Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion is a strong acid and at least one high volatility counterion is a weak acid. 挥发性弱酸平衡离子具有至少一个高于约2的pKa和在Patm下低于约50°C的熔点或者低于约170°C的沸点。 Volatile weak acid counterions having a pKa of at least about 2 and a melting point less than about the boiling point of 50 ° C or below at Patm higher than about 170 ° C. 此类酸的实例包括乙酸、丙酸、戊酸 Examples of such acids include acetic acid, propionic acid, pentanoic acid

坐坐寸寸ο Begins to sit ο

[0142] 酸性平衡离子可以以中和在制剂pH下药物上存在的正电荷所需的量存在。 [0142] an acidic counterion may be present in an amount required to neutralize the positive charge present on the pH of the pharmaceutical formulation. 可以将过量平衡离子(作为游离酸或者盐)加入药物中以控制PH和提供足够缓冲能力。 Excess counterion may be (as the free acid or a salt thereof) added to the drug to provide adequate control and PH buffering capacity.

[0143] 在本发明的一个实施方案中,涂层制剂包括至少一种抗氧化剂,其可以是螯合剂,如柠檬酸钠、柠檬酸、EDTA(乙二胺四乙酸)或者自由基清除剂,如抗坏血酸、甲硫氨酸、抗坏血酸钠,等等。 [0143] In one embodiment of the present invention, the coating formulations include at least one antioxidant, which can be a chelating agent, such as sodium citrate, citric acid, EDTA (ethylenediaminetetraacetic acid) or free radical scavengers, such as ascorbic acid, methionine, sodium ascorbate, and the like. 当前优选的抗氧化剂包括EDTA和甲硫氨酸。 Currently preferred antioxidants include EDTA and methionine.

[0144] 在本发明的一个实施方案中,涂层制剂包括至少一种表面活性剂,其可以是两性离子的、兼性的、阳离子的、阴离子的或者非离子表面活性剂,包括但不限于,月桂酰两性基乙酸钠、十二烷基硫酸钠(SDS)、十六烷基氯化吡啶鎗(CPC)、十二烷基三甲基氯化铵(TMAC)、盐酸胱胺、氯化物、聚山梨酸酯(如Tween20和Tween80)、其他山梨聚糖衍生物(如失水山梨糖醇月桂酸酯)和烷氧基化醇(如聚乙二醇单十二醚4)。 [0144] In one embodiment of the present invention, the coating formulations include at least one surfactant, which may be, facultative zwitterionic, cationic, anionic or non-ionic surfactants, including, but not limited to, , lauroampho sodium acetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride gun (CPC), dodecyltrimethylammonium chloride (of TMAC), cysteamine hydrochloride, chloride , polysorbates (such as Tween20 and Tween 80), other sorbitan derivatives (e.g., sorbitan laurate), and alkoxylated alcohols (e.g. polyethylene glycol monolauryl ether 4).

[0145] 在本发明的另一实施方案中,涂层制剂包括具有两亲性质的至少一种聚合物材料或者聚合物,其可以包含,但不限于,纤维素衍生物,如羟乙基纤维素(HEC)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、甲基纤维素(MC)、羟乙基甲基纤维素(HEMC)、或者乙基羟基-乙基纤维素(EHEC)以及普流罗尼。 [0145] In another embodiment of the present invention, the coating formulations include at least one polymeric material or polymer that has amphiphilic properties, which may include, but are not limited to, cellulose derivatives such as hydroxyethyl cellulose Su (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxyethyl methyl cellulose (HEMC), or ethylhydroxy - b cellulose (EHEC), and pluronics.

[0146] 在另一实施方案中,涂层制剂包括亲水聚合物,其选自下面的组:羟乙基淀粉、葡聚糖、聚(乙烯醇)、聚(环氧乙烷)、聚(甲基丙烯酸2-羟基乙酯)、聚(正乙烯吡咯烷酮)、聚乙二醇和它们的混合物,和类似聚合物。 [0146] In another embodiment, the coating formulation includes a hydrophilic polymer selected from the following group: hydroxyethyl starch, dextran, poly (vinyl alcohol), poly (ethylene oxide), poly (2-hydroxyethyl methacrylate), poly (n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and like polymers.

[0147] 在本发明的另一实施方案中,涂层制剂包括生物相容性载体,其可以包括,但不限于,人清蛋白、生物工程化人清蛋白、聚谷氨酸、聚天冬氨酸、聚组氨酸、多硫酸戊聚糖、聚氨基酸、蔗糖、海藻糖、松三糖、棉子糖和水苏糖。 [0147] In another embodiment of the present invention, the coating formulation includes a biocompatible carrier, which may include, but are not limited to, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffinose and stachyose.

[0148] 在另一实施方案中,涂层制剂包括稳定剂,其可以包含,但不限于,非还原糖、多糖或者还原糖。 [0148] In another embodiment, the coating formulation includes a stabilizing agent, which may include, but are not limited to, non-reducing sugar, a polysaccharide or a reducing sugar. 用于本发明的方法和组合物中的适宜的非还原糖包括,例如,蔗糖、海藻糖、水苏糖或者棉子糖。 Suitable non-reducing sugars used in the methods and compositions of the present invention include, for example, sucrose, trehalose, stachyose, or raffinose. 用于本发明的方法和组合物中的适宜的多糖包括,例如,葡聚糖、可溶性淀粉、糊精和胰岛素。 Methods and compositions of the present invention suitable polysaccharides include, for example, dextran, soluble starch, dextrin, and insulin. 用于本发明的方法和组合物中的适宜的还原糖包括,例如,单糖,例如,芹菜糖、阿拉伯糖、来苏糖、核糖、木糖、洋地黄毒糖、岩藻糖、栎醇、鸡纳糖、鼠李糖、阿洛糖、阿卓糖、果糖、半乳糖、葡萄糖、古洛糖、金缕梅糖、艾杜糖、甘露糖、塔格糖等等;和二糖,如樱草糖、荚豆二糖、芸香糖、绵枣儿二糖、纤维二糖、龙胆二糖、乳糖、乳果糖、麦芽糖、蜜二糖、槐二糖和松二糖等等。 The methods and compositions used in the present invention Suitable reducing sugars include, e.g., monosaccharides, e.g., apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol , chicken satisfied, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, witch hazel, idose, mannose, tagatose, and the like; and disaccharides, such as primrose sugar, bean pods disaccharide, rutin sugar, Scilla disaccharide, cellobiose, gentian disaccharide, lactose, lactulose, maltose, melibiose, locust and pine disaccharide disaccharide and so on.

[0149] 在另一实施方案中,涂层制剂包括血管收缩剂,其可以包含,但不限于,阿米福林、咖啡氨醇、甲环戊丙胺、去氧肾上腺素、肾上腺素、苯赖加压素、茚咪唑啉、甲噻嗯唑啉、甲氧胺福林、萘唑林、盐酸异肾上腺素、异辛胺、鸟氨酸加压素、羟甲唑啉、苯福林、苯乙醇胺、苯丙醇胺、环己丙甲胺、假麻黄碱、四氢唑啉、萘胺唑啉、庚胺、麝草唑啉、血管加压素、丁苄唑啉和它们的混合物。 [0149] In another embodiment, the coating formulation includes a vasoconstrictor, which can comprise, without limitation, amidephrine, coffee sphingosine, cyclopentyl methyl amine, phenylephrine, epinephrine, benzene Lai vasopressin, indene imidazoline, oxazoline A thiazole ah, methoxyamine phenylephrine, naphthalene cefazolin, epinephrine hydrochloride isopropyl, iso-octylamine, ornithine vasopressin, oxymetazoline, phenylephrine, benzene ethanolamine, phenylpropanolamine, propylhexedrine cycloalkyl, pseudoephedrine, tetrahydrozoline, naphthylamine oxazoline, heptyl amine, oxazoline musk grass, vasopressin, xylometazoline and mixtures thereof. 最优选的血管收缩剂包括肾上腺素、萘唑林、四氢唑啉、茚咪唑啉、甲噻嗯唑啉、萘胺唑啉、麝草唑啉、羟甲唑啉和丁苄唑啉。 The most preferred vasoconstrictors include epinephrine, naphthalene cefazolin, tetrahydrozoline, indene imidazoline, oxazoline ah A thiazole, oxazoline naphthylamine, musk grass oxazoline, oxymetazoline and xylometazoline.

[0150] 如本领域技术人员将理解的,向涂层制剂加入血管收缩剂和因此本发明的固体生物相容的涂层可以尤其用于防止应用微突出物装置或者阵列后的出血,以及通过减小应用部位的血流和降低从皮肤部位向全身循环的吸收速率而延长活性剂的药物代谢动力学。 [0150] As will be appreciated by those skilled in the art, the solid biocompatible coating is added to the coating formulation vasoconstrictor and thus the present invention may be particularly useful to prevent bleeding after applying the microprojection devices or arrays, and by reduced blood flow and reduced the area of ​​application of the active agent from the extended portion of the skin to the systemic circulation rate of absorption pharmacokinetics.

[0151] 在本发明的另一实施方案中,涂层制剂包括至少一种“途径开放调节剂”,其可以包含,但不限于,渗透性试剂(例如,氯化钠)、两性离子化合物(例如,氨基酸)和消炎药,如倍他米松21-磷酸二钠盐、醋酸去炎松21-磷酸二钠、盐酸氢可他酯、氢化可的松21-磷酸二钠盐、甲基氢化泼尼松21-磷酸二钠盐、甲基氢化泼尼松21-琥珀酸钠盐、对氟米松磷酸酯二钠和强的松龙21-琥珀酸钠盐,和抗凝血剂,如柠檬酸、柠檬酸盐(例如,柠檬酸钠)、硫酸糊精钠、阿司匹林和EDTA。 [0151] In another embodiment of the present invention, the coating formulations include at least one "pathway patency modulator", which can comprise, without limitation, osmotic agents (e.g., sodium chloride), zwitterionic compounds ( For example, amino acids), and anti-inflammatory agents, such as betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21- disodium phosphate, hydrocortamate hydrochloride him esters, hydrocortisone 21-phosphate disodium salt, methyl hydrogen splashed prednisolone 21-phosphate disodium salt, methylprednisolone 21-succinate sodium salt, paramethasone disodium phosphate and fluoride prednisolone 21-succinate sodium salt, and anticoagulants, such as citric acid , citrate (e.g., sodium citrate), dextrin sulfate sodium, aspirin and EDTA.

[0152] 在本发明的再一个实施方案中,涂层制剂包括增溶/络合剂,其可以包含α -环糊精、β -环糊精、Y -环糊精、葡糖基-α -环糊精、麦芽糖基-α -环糊精、葡糖基-β -环糊精、麦芽糖基-β -环糊精、羟丙基β -环糊精、2-羟丙基-β -环糊精、2-羟丙基-Y -环糊精、羟乙基-β -环糊精、甲基-β -环糊精、磺丁基醚-α -环糊精、磺丁基醚-β -环糊精和磺丁基醚-Y-环糊精。 [0152] In a further embodiment of the present invention, the coating formulation includes a solubilising / complexing agent, which may comprise α - cyclodextrin, β - cyclodextrin, Y - cyclodextrin, glucosyl -α - cyclodextrin, maltosyl [alpha - cyclodextrin, glucosyl-yl [beta] -D - cyclodextrin, maltosyl [beta] -D - cyclodextrin, hydroxypropyl beta] - cyclodextrin, 2-hydroxypropyl [beta] -D - cyclodextrin, 2-hydroxypropyl -Y - cyclodextrin, hydroxyethyl -β - cyclodextrin, methyl -β - cyclodextrin, sulfobutyl ether -α - cyclodextrin, sulfobutyl ether -β - -Y- cyclodextrin and sulfobutyl ether cyclodextrin. 最优选的增溶/络合剂为环糊精、羟丙基环糊精、2-羟丙基-β -环糊精和磺丁基醚7 β -环糊精。 The most preferred solubilising / complexing agent is a cyclodextrin, hydroxypropyl-cyclodextrin, 2-hydroxypropyl -β - cyclodextrin and sulfobutyl ether 7 β - cyclodextrin.

[0153] 在本发明的另一实施方案中,涂层制剂包括至少一种非水溶剂,如乙醇、异丙醇、甲醇、丙醇、丁醇、丙二醇、二甲基亚砜、甘油、N,N- 二甲基甲酰胺和聚乙二醇400。 [0153] In another embodiment of the present invention, the coating formulations include at least one non-aqueous solvent, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethylsulfoxide, glycerol, N , N- dimethylformamide and polyethylene glycol 400.

[0154] 优选地,涂层制剂具有小于约500厘泊且大于约3厘泊的粘度。 [0154] Preferably, the coating formulations have a viscosity less than approximately 500 centipoise and greater than about 3 centipoise.

[0155] 在本发明的一个实施方案中,如通过从微突出物表面测量的,生物相容性涂层的厚度小于25微米,更优选小于10微米。 [0155] In one embodiment of the invention, as measured from the surface through the micro-projections, the thickness of the biocompatible coating is less than 25 microns, more preferably less than 10 microns.

[0156] 给出下面的实施例以使得本领域技术人员能够更清楚地理解和实施本发明。 [0156] The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. 不应将它们理解为限制本发明的范围,而应理解为仅仅是作为本发明的代表阐明的。 They should not be construed as limiting the scope of the invention, but should be construed only as representative of the present invention is set forth. 已经设计了一种方法用以计算多肽和其他电解质中离子种类的分布。 A method has been devised for calculating polypeptides and other ionic species in the electrolyte distribution. 多年来己可以利用用于平衡计算的方程。 For many years already we may utilize calculation of the equilibrium equation. 它们基于经典平衡定律。 They are based on the classical equilibrium. 它们可以成功地用于计算聚电解质如多肽的净电荷以及蛋白质的P〗。 They may be successfully used to calculate P〗 polyelectrolyte as net charge of polypeptides and proteins. 净电荷和Pi计算是表征和纯化多肽的有效工具。 And Pi are calculated net charge and effective tool to characterize the purification of the polypeptide. 然而,这些计算不产生关于存在于特定PH下溶液中的种类的直接信息。 However, these calculations do not have direct information about the species present in a particular solution of the PH. 例如,从这些方法不能预测其中存在怀疑具有低溶解性的种类的PH范围。 For example, these methods can not be predicted from the presence of suspected PH range wherein a low solubility type. 已经进行了多种尝试以估计聚电解质中不同离子形式之间的平衡° 这些尝试已经由Edsall JT(Proteins as acidsand bases, in proteins, aminoacids and peptides as ions and dipolarions, Cohn EJ& Edsall JT编著;HafnerPub ;New York andLondon, 1943,444-505)概述。 Have been many attempts to estimate the balance ° between polyelectrolytes in different ionic forms of these attempts have been made Edsall JT (Proteins as acidsand bases, in proteins, aminoacids and peptides as ions and dipolarions, Cohn EJ & Edsall JT eds; HafnerPub; New York andLondon, 1943,444-505) Overview.

[0157] 最成功的方法描述了独立离子化的基团的系统的概率分布函数。 Probability [0157] The most successful approach described system is independent of the ionizable groups of the distribution function. 在该处理中,多种基团通过类别分类,每个类相应于一个PKa值。 In this process, the various groups by classification, each class corresponding to a PKa value. 该方法有点麻烦并且不容易实现自动化计算。 This method is a little cumbersome and not easy to automate calculations. 此外,计算局限于净电荷种类并且不包括描述分子内的电荷分布。 Further, the calculation is not limited to the net charge type and includes a charge distribution within the molecule is described. 令人惊奇地,对于聚电解质而言,对存在于溶液中的实际种类的浓度很少关注。 Surprisingly, for the polyelectrolyte, the actual concentration of species present in the solution of little concern. 这似乎是缺少描述存在重叠口1值时种类分布的方程所导致的,所述重叠pKa值即为通过小于约3pH单位分开的两个或更多个口1值。 This seems to be a lack of equations describing the species distribution of the value of the overlapping opening 1 is caused, namely the overlapping pKa value less than a value obtained by a separate unit 3pH about two or more ports 1. 在该情况中,用近似值计算种类的分布。 In this case, the kind of distributed computing by approximation. 在多肽分子中,其中10个以上重叠的PKa值是常见的,基于这些近似值的计算是不实际的并且当然将产生错误结果。 Polypeptide molecules in which more than 10 are common overlapping PKa value based on the approximation calculation is not practical and would certainly produce incorrect results. 结果,显然还没有描述多肽中种类的分布。 As a result, clearly not in the distribution of the type described polypeptides. 已经设计了一种方法,其提供描述任何聚电解质的种类分布的方程,前提是它们的PKa值是已知的。 A method has been devised, which provides a description of any equation polyelectrolyte species distribution, provided that they are known PKa values. 还提供了进行这些计算的计算算法。 Also it provides a computing algorithm for these calculations.

[0158] 方法 [0158] Method

[0159] 对于多肽,有关酸-碱基和它们的pKa值分别为:末端羧基,PKa = 3.05 ;天冬氨酸的β -羧基,PKa = 3.93 ;谷氨酸的Y -羧基,pKa = 4.43 ;半胱氨酸的巯基,pKa = 8.38 ;酪氨酸的酚,PKa = 10.36 ;组氨酸的咪唑鎗盐,pKa = 5.96 ;末端铵,pKa = 8.1 ;赖氨酸的ε -铵,PKa = 10.59 ;精氨酸的胍基,pKa = 12.48。 [0159] For polypeptides, related to the acid - base and pKa values ​​thereof are: the terminal carboxyl group, PKa = 3.05; aspartic acid beta] - carboxy, PKa = 3.93; the Y-glutamic acid - carboxyl, pKa = 4.43 ; cysteine ​​thiol group, pKa = 8.38; tyrosine phenol, PKa = 10.36; histidine imidazole salt gun, pKa = 5.96; end ammonium, pKa = 8.1; lysine ε - ammonium, PKa = 10.59; arginine guanidino, pKa = 12.48. 上面的pKa值是从文献汇编的平均值并且用于实施例中。 The above document from the average pKa value is compiled and used in the Examples. 从它们的PKa值计算的分子的净电荷曲线外推pi值。 Outer curve calculated from the net charge of their molecular push the PKa value of pi.

[0160] 确定聚电解质中的种类浓度 [0160] determining the concentration of polyelectrolyte species

[0161] 对于弱酸AH,平衡可以写作: [0161] For weak acid AH, balance can be written as:

[0162] [0162]

AH 二 A'+ H+ AH two A '+ H +

[0163] 其解离常数为: [0163] with a dissociation constant:

[0164] Ka = (Al X (H+) / (AH) [0164] Ka = (Al X (H +) / (AH)

[0165] (A_)、(H+)和(AH)是这些种类的各自浓度。 [0165] (A _), (H +) and (AH) is the concentration of each of these species.

[0166] 根据上面的,可以得到经典Henderson-Hasselbalch方程: [0166] According to the above can be obtained by classical Henderson-Hasselbalch equation:

[0167] pH = pKa+Log ((PC) / (AH)) [0167] pH = pKa + Log ((PC) / (AH))

[0168] 假设:(A_) + (AH) = I,则该方程得到: [0168] assumptions: (A_) + (AH) = I, the equation:

[0169] 中性摩尔份数=i/(ι+ιο«) = P [0169] Neutral molar fraction = i / (ι + ιο «) = P

[0170] 其也可以定义为酸为中性的概率。 [0170] It may also be defined as the probability that the acid is neutral. 类似地: Similarly:

[0171] 离子化、带负电的摩尔份数=l_l/(l+10pH_pKa) = 1-P [0171] ionization, negatively charged molar fraction = l_l / (l + 10pH_pKa) = 1-P

[0172]净电荷=l/(l+10pH_pKa)-l。 [0172] Net charge = l / (l + 10pH_pKa) -l.

[0173] 对于弱碱B,平衡可以写作: [0173] For a weak base B, the balance can be written as:

[0174] [0174]

B+H+ ' ■ , BH+ B + H + '■, BH +

[0175] 其解离常数为: [0175] with a dissociation constant:

[0176] Ka = (B) X (H+) / (BH+) [0176] Ka = (B) X (H +) / (BH +)

[0177] 类似地: [0177] Similarly:

[0178] pH = pKa-Log (BH+/B), [0178] pH = pKa-Log (BH + / B),

[0179]中性摩尔份数=l/(l+10pKa_pH) = Q [0179] mole fraction of neutral = l / (l + 10pKa_pH) = Q

[0180] 离子化、带正电荷的摩尔份数=l_l/(l+10pKa_pH) = 1-Q, [0180] ionized, the positively charged molar fraction = l_l / (l + 10pKa_pH) = 1-Q,

[0181]净电荷=ll/(l+10pKa-pH) [0181] Net charge = ll / (l + 10pKa-pH)

[0182] 这些种类定义为溶液中化合物的酸性功能和碱性功能的电荷的所有可能的组合。 [0182] All possible combinations of basic charge and an acidic function defined as functions of these classes of compounds in the solution. 例如,如果化合物仅呈现酸性功能,那么种类取像(Γ、Γ、2.等的值。类似地,如果化合物仅呈现碱性功能,那么种类取像O+、1+、2+等的值。如果化合物具有酸性和碱性功能,那么种类取0_0+、0_1+、1_0+、1_1+等的值。净带电种类定义为呈现相同净电荷的所有种类的总和。它们取值:..._2、-1>0> +1、+2...。 For example, if the compound presents only acidic functionality, the species take (Γ, Γ, 2. Other values ​​like. Similarly, if the compound presents only a basic function, then the type of imaging O +, +, the value of 2 + like 1. If the compound having both acidic and basic functionality, then take the kind + 0_0, 0_1 + + 1_0, 1_1 + value of the net charged species such as defined as the sum of all present the same kind of net charge values ​​are: 2 ..._, -1> 0> + 1, + 2 ....

[0183] 对于具有一个酸性(带负电)化合物,在任意pH下存在于溶液中的种类为:0_和1_(一个种类是中性的:无正电荷并且无负电荷;其他种类具有一个正电荷并且无负电荷)。 [0183] (negatively charged) for having one acidic compound, species present in the solution at any pH as: 0_ and (1_ is a neutral species: No negative charge and no positive charges; other species having a positive charge and no negative charge). P1是酸性基团为中性的概率,在特定pH下这些种类的摩尔份数为: P1 is an acidic group is neutral probability, at a particular pH is the mole fraction of these species:

[0184] 011 [0184] 011

[0185] Γ J-P1 [0185] Γ J-P1

[0186] 对于具有一个酸性pKa和一个碱性(带正电)PKJ^化合物,存在于特定pH下溶液中的种类为0-0+、0-Γ、Γ0+、Γ1+1。 [0186] For a one acidic pKa and a basic (positively charged) PKJ ^ compound type present in the solution is 0-0 +, 0-Γ specific pH, Γ0 +, Γ1 + 1.

[0187] P1和Q1分别是酸性和碱性基团为中性的概率,在特定pH下这些种类的摩尔份数为: [0187] P1 and Q1 are the acidic and basic groups neutral probability, at a particular pH is the mole fraction of these species:

[0188] (TO+=P1XQ1 [0188] (TO + = P1XQ1

[0189] OH1X(1-Q1) [0189] OH1X (1-Q1)

[0190] Γ0+: (1-P1) XQ1 [0190] Γ0 +: (1-P1) XQ1

[0191] ΓΓ: (1-P1) X (1-P1) [0191] ΓΓ: (1-P1) X (1-P1)

[0192] 对于具有一个酸性pKa和两个碱性pKa的化合物,任一pH下溶液中存在的种类为(Γ0+、(η+、(Γ2+、Γ0+、ΓΓ、Γ2+。 [0192] For compounds having one acidic and two basic pKa pKa of any type present in the solution at a pH of (Γ0 +, (η +, (Γ2 +, Γ0 +, ΓΓ, Γ2 +.

[0193] P1是酸性基团为中性的概率,且Q1和Q2是碱性基团为中性的概率,特定pH下这些种类的摩尔份数为: [0193] P1 is an acidic group is neutral probability, and Q1 and Q2 is a basic group neutral probability, the mole fraction of these species at a specific pH is:

[0194] O^O+ =P1XQ1XQ2 [0194] O ^ O + = P1XQ1XQ2

[0195] OT: (P1XQ1X (1-Q2)) + (P1X (1-Q1) X Q2) [0195] OT: (P1XQ1X (1-Q2)) + (P1X (1-Q1) X Q2)

[0196] 0_2+ =P1 X (1-Q1) X (1-Q2) [0196] 0_2 + = P1 X (1-Q1) X (1-Q2)

[0197] Γ0+: (1-P1) XQ1XQ2 [0197] Γ0 +: (1-P1) XQ1XQ2

[0198] Γ1+: ((1-P1) XQ1X (1-Q2)) + ((1-P1) X (1-Q1) X Q2) [0198] Γ1 +: ((1-P1) XQ1X (1-Q2)) + ((1-P1) X (1-Q1) X Q2)

[0199] I 2+: (1-P1) XX (1-Q1) X (1-Q2)等等。 [0199] I 2+: (1-P1) XX (1-Q1) X (1-Q2) and the like.

[0200] 可以看到,有(N+l) (M+1)个种类,N和M分别为酸性和碱性pKa的数目。 [0200] can be seen, there are a number of acidic and basic pKa (N + l) (M + 1) species, N and M. 在前面的实例中,有6个可能种类。 In the previous example, there are six possible types. 可能的净电荷种类为_1、0、+1、+2。 Possible types _1,0 net charge of + 1, + 2. 可能的净电荷种类的数为(N+M+1)。 Possible types of net charge number (N + M + 1). 可以容易地推导在特定pH下这些净带电种类的摩尔份数。 It can be easily derived mole fraction of the net charged species at a particular pH. 使用前面的实例: The preceding Example:

[0201] -1 =(1-P1) XQ1XQ2 [0201] -1 = (1-P1) XQ1XQ2

[0202] O: (P1X Q1X Q2) + ((1-P1) XQ1X (1-Q2)) + ((1-P1) X (1-Q1) X Q2) [0202] O: (P1X Q1X Q2) + ((1-P1) XQ1X (1-Q2)) + ((1-P1) X (1-Q1) X Q2)

[0203] +1 =P1 XQ1X (1-Q2)) + (P1X (1-Q1) X Q2) + (1-P1) XX (1-Q1) X (1-Q2) [0203] +1 = P1 XQ1X (1-Q2)) + (P1X (1-Q1) X Q2) + (1-P1) XX (1-Q1) X (1-Q2)

[0204] +2 =P1X (1-Q1) X (1-Q2) [0204] +2 = P1X (1-Q1) X (1-Q2)

[0205] 聚电解质的种类和化合价的计算算法: [0205] species and valences calculation algorithm polyelectrolytes:

[0206] 基于上面的方程,已经得到了用于计算聚电解质中存在的电荷、净电荷、种类和化合价的算法。 [0206] Based on the above equations, has been used to calculate the charge present in the polyelectrolyte, net charge, the type and valency algorithm. 在下面,粗体和大写字母表示向量或者矩阵,小写字母代表向量或者矩阵的元素。 In the following, bold capital letters, and a vector or a matrix, vector or small letters element matrix.

[0207] 假设我们已知化合物中具有N个酸性功能和M个碱性功能,则给出了它们的pKa值,并且还给出了溶液的pH值。 [0207] Suppose we are known compounds having an acidic function of N and M basic function, given their pKa values, and also gives the pH of the solution. 设PKAa为酸性pKa值的NX I向量,且PKAb为碱性pKa值的MX I向量: NX I vector is set PKAa pKa value of the acidic and basic vector PKAb of MX I pKa values:

[0208] PKAa = (pKaal, pKaa2, , pKa^)τ [0208] PKAa = (pKaal, pKaa2,, pKa ^) τ

[0209] PKAb = (pKabl, pKab2, , pKabM)T [0209] PKAb = (pKabl, pKab2,, pKabM) T

Figure CN1842320BD00221

[0214] 其中P和Q分别是酸性组分和碱性功能中性的摩尔份数。 [0214] wherein P and Q are the molar fraction of acidic components and basic functions neutral. 它们还可以理解为酸或碱中性的概率。 They can also be understood as neutral probability acid or base. 让电荷3表示酸的电荷的NX I向量,而电荷b为碱的MX I向量: 3 represents the charge so that the charge NX I acid vector, b is the base and the charge vectors MX I:

[0215] [0215]

Figure CN1842320BD00222

[0220] 其中净电荷为溶液中络合分子的电荷。 [0220] wherein the net charge of a charge complex molecules in solution.

[0221] 接着,让我们考虑分子化合物的种类。 [0221] Next, let us consider the kind of molecular compounds. 为了简单起见,我们用α代表种类。 For simplicity, we use α represents the species. 为了理解种类计算算法,我们从简单的情况开始。 To understand the kind of calculation algorithm, we start with a simple situation. 假设化合物仅有N种酸,我们则想得到溶液中α的概率。 N is assumed that only one acid compound, the probability that we want the solution is α. 基于上面的推导,P为酸为中性的概率向量。 Based on the above derivation, P is a probability vector acid is neutral. 让我们考虑统计学实验。 Let us consider the statistical test. 假如通过一种接一种地加入酸得到溶液中的化合物。 If compound solution by means of a an earth ground is added to give an acid. 在开始时,仅向溶液中加入一种酸,我们有: In the beginning, only adding an acid to the solution, we have:

[0222] Prob ( α = Cf, I 酸)=P1 [0222] Prob (α = Cf, I acid) = P1

[0223] (6) [0223] (6)

[0224] Prob ( α = Γ, I 酸)=1-P1 [0224] Prob (α = Γ, I acid) = 1-P1

[0225] (7) [0225] (7)

[0226] Prob ( α =2、I 酸)=...= [0226] Prob (α = 2, I acid) = ... =

[0227] = Prob ( α =『,1 酸)=0 [0227] = Prob (α = ", 1 acid) = 0

[0228] (8) [0228] (8)

[0229] 然后假设我们在溶液中已经有i种酸,并之后再加入一种酸。 [0229] Then assume that we have the i in the acid solution, and then adding an acid. 概率关系为: Probability relationship:

[0230] Prob ( α = Cf, i+1 酸) [0230] Prob (α = Cf, i + 1 acids)

[0231] = Prob ( α = Cf, i 酸| 第(i+1)种酸=O) Prob (第i+1 种酸=O) [0231] = Prob (α = Cf, i acid | of the (i + 1) kinds of acid = O) Prob (i + 1-one acid = O)

[0232] Prob ( a = y, i+1 酸) [0232] Prob (a = y, i + 1 acids)

[0233] = Prob ( = j、i 酸I 第(i+1)种酸=O) Prob (第i+Ι 种酸=O) [0233] = Prob (= j, i of the acid I (i + 1) kinds of acid = O) Prob (the first acid species i + Ι = O)

[0234] +Prob ( a = (j-1)-, i 酸| 第(i+1)种酸=I) Prob (第i+Ι 种酸=I) [0234] + Prob (a = (j-1) -, i acids | of the (i + 1) kinds of acid = I) Prob (the first acid species i + Ι = I)

[0235] 这里,我们假设所有酸都是独立的,因此我们可以改写上面的方程: [0235] Here, we assume that all the acid are independent, we can rewrite the above equation:

[0236] Prob ( α = Cf, i+1 酸) [0236] Prob (α = Cf, i + 1 acids)

[0237] = Prob ( α = Cf, i 酸)Prob (第i+Ι 种酸=O) [0237] = Prob (α = Cf, i acids) Prob (the first acid species i + Ι = O)

[0238] (9)[0239] Prob ( α = j、i+1 酸) [0238] (9) [0239] Prob (α = j, i + 1 acids)

[0240] = Prob ( α = j-, i 酸)Prob (第i+1 种酸=O) [0240] = Prob (α = j-, i acids) Prob (i + 1-one acid = O)

[0241] +Prob ( α = (j_l)-, i 酸)Prob (第i+1 种酸=I) [0241] + Prob (α = (j_l) -, i acids) Prob (i + 1-one acid = I)

[0242] (10) [0242] (10)

[0243] 方程(9)和(10)使得我们可以容易地计算概率。 [0243] Equation (9) and (10) so that we can easily calculate the probability. 为了实现它们,设R为(N+l) XN矩阵: To achieve them, provided R is (N + l) XN matrix:

[0244] r[j, i] = Prob ( α = (jl)、i 酸) [0244] r [j, i] = Prob (α = (jl), i acid)

[0245] 我们可以将(6)、(7)、⑶、(9)和(10)改写作: [0245] We can (6), (7), ⑶, (9) and (10) to change the writing:

[0246] r[l,l] = P1 (11) [0246] r [l, l] = P1 (11)

[0247] r[2,l] = 1-P1 (12) [0247] r [2, l] = 1-P1 (12)

[0248] r[3,1] =...= r[N+l, I] = 0 (13) [0248] r [3,1] = ... = r [N + l, I] = 0 (13)

[0249] r[I, i+1] = r[I, i]Pi+1 (14) [0249] r [I, i + 1] = r [I, i] Pi + 1 (14)

[0250] r[j+l, i+1] = r[j+l, i]Pi+1+r[j, i] (1-Pi+1) [0250] r [j + l, i + 1] = r [j + l, i] Pi + 1 + r [j, i] (1-Pi + 1)

[0251] (15) [0251] (15)

[0252] i = 1...(N-1),j = 1,...,N [0252] i = 1 ... (N-1), j = 1, ..., N

[0253] 可以非常直接地通过循环编码上面的递归算法,且R的最后一列仅代表当具有N种酸的化合物存在于溶液中时种类的概率。 Compound [0253] can be encoded by circulating very directly above recursive algorithm, and the last one represents R when having only one acid is present in the N probability of species in solution. 不丧失一般性时,设A为R的最后列。 Without loss of generality, it is assumed for the last column of R A. 类似地,当M种碱的化合物存在于溶液中时,设B为种类概率向量,并且维数为(M+1)X1。 Similarly, when the base compound M species present in the solution, provided B is a probability vector type, dimension and number (M + 1) X1. B的计算遵循与A的相同法则。 The calculated B to A follows the same rules. 如果化合物具有N种酸和M种碱,那么种类的概率为: If an acid and a compound having M N kinds of alkali species, then the probability of the type:

[0254] C = AXBt (16) [0254] C = AXBt (16)

[0255] c [i, j] = Prob ( a = (i_l)-(j_l)+) (17) [0255] c [i, j] = Prob (a = (i_l) - (j_l) +) (17)

[0256] i = 1,2,…,N+l [0256] i = 1,2, ..., N + l

[0257] j = 1,2,..., M+1 [0257] j = 1,2, ..., M + 1

[0258] 其中C为(N+l) X (M+1)矩阵。 [0258] where C is the (N + l) X (M + 1) matrix. 最后,可以基于C构造净电荷种类(β): Finally, the net charge can be configured based on the type C (β):

Figure CN1842320BD00231

[0260]其中 i =-N,...,_1,0,1,...,M [0260] where i = -N, ..., _ 1,0,1, ..., M

[0261] 基于上面的,可以计算所选化合物的带电或者中性种类的分布,其在下面的实例中阐明。 [0261] Based on the above, a charged or neutral species can be calculated for selected compounds of the distribution, which in the example set forth below.

[0262] 实施例1: [0262] Example 1:

[0263] 图1显示了作为pH函数的乙酸(pKa4.75)的电荷特征。 [0263] FIG. 1 shows the acid charge as a function of pH (pKa4.75) features. 在低于约2.5的pH下,乙酸的羧基被完全质子化,从而分子上没有电荷。 At a pH less than about 2.5, acetic acid carboxyl group is fully protonated, so that no charge on the molecule. 随着PH从约2.5增加到约7,一个或多个羧基部分变为离子化的,从而形成带负电的乙酸盐离子。 PH 7 with from about one to about 2.5 or more carboxyl moieties increases becomes ionized, thereby forming a negatively charged acetate ion. 在约PH7时,所有羧基都被离子化。 At about PH7, all carboxyl groups are ionized.

[0264] 图2显示了乙酸和乙酸盐的摩尔比。 [0264] FIG. 2 shows the molar ratio of acetic acid and acetate. 在pHO时,随着乙酸的羧基完全质子化,基本上仅有乙酸,从而摩尔份数为I。 When pHO, with the carboxyl group of fully protonated acid, acetic acid substantially only to mole fraction is I. 在约PH2.5,开始羧基的离子化,并且图中代表乙酸的实线曲线开始向下移动。 About PH2.5, carboxy start ionization and FIG acid solid line represents the curve starts to move downward. 同时,代表离子化乙酸盐的虚线开始向上移动离开0.00线。 Meanwhile, representative of ionized acetate 0.00 broken line start upward movement away from the line. 在约pH4.7时,有相等数目的带电和不带电部分。 At about pH4.7, an equal number of charged and uncharged portions. 在大于约7的pH时,不再有任何不带电的乙酸,并且基本上所有种类都是带电的乙酸盐离子。 At a pH greater than about 7, there is no longer any uncharged acetic acid, and substantially all of the charged species are acetate ions.

[0265] 许多药物当为带电状态时在水中显示出最大溶解性。 [0265] Many drugs showed a maximum when the solubility in water is charged state. 图3显示了具有一种碱性pKa(8.5)的小分子量弱碱性药物芬太尼的电荷特征。 Figure 3 shows the charge characteristics having one basic pKa (8.5) of small molecular weight weakly basic drug fentanyl. 在低于6的pH下,基本上所有芬太尼都带正电,而在高于11的PH下,基本上所有芬太尼都是中性的。 At a pH below 6, substantially all of the fentanyl are positively charged, while at a PH of greater than 11, substantially all of the fentanyl are neutral.

[0266] 图4显示了不同pH下中性(芬太尼碱-实线)和带电芬太尼(芬太尼+1 -虚线)种类的摩尔比。 [0266] Figure 4 shows the different pH neutral (fentanyl base - solid line) - the molar ratio of the charged species and fentanyl (fentanyl broken line 1). 从PHO到约pH6,基本上没有芬太尼碱存在并且100%都是带电芬太尼+1。 From PHO to about pH6, and substantially no presence of 100% of fentanyl base were charged fentanyl +1. 从pH约6到约pHll,存在转变。 A pH of from about 6 to about pHll, there is a transition. 芬太尼+1以与芬太尼碱增加的相同速率减小。 Fentanyl and fentanyl base +1 decreased to increase at the same rate. 在或者高于PHl I时,基本上所有芬太尼都以不带电的、中性芬太尼碱存在。 At or above the PHl I, substantially all of the fentanyl are uncharged, neutral presence of fentanyl base.

[0267] 复杂分子如肽和蛋白质也显示出带电特征,其取决于pH。 [0267] complex molecules such as proteins and peptides also show the charging characteristics, depending on pH. 图5显示了hPTH(l_34)的电荷特征,hPTH(l-34)是具有11种碱性pKa和6种酸性pKa的肽。 Figure 5 shows hPTH (l_34) charge characteristics, hPTH (l-34) is a peptide having 11 kinds of basic pKa pKa of the acid and 6. 在pH9时,肽具有O净电荷。 At pH9, O peptide has a net charge. 该点也称作等电点或者pi。 This point is also called the isoelectric point or pi.

[0268] 图6显示了PTH的净电荷种类的摩尔比。 [0268] FIG. 6 shows a net charge molar ratio of PTH species. 所述种类在+11电荷到_6电荷范围内。 The species to the +11 charge _6 charge range. 中性种类仅在约6到约11.5的pH范围内以显著量存在。 The neutral species only exist in significant amounts in the pH range from about 6 to about 11.5. 在该pH范围内,PTH从溶液沉淀出来。 In this pH range, PTH precipitate out of solution.

[0269] 图7显示了乙酸芬太尼(虚线)、乙酸(实线)和芬太尼的中性形式(芬太尼碱-点线)的摩尔比。 [0269] FIG. 7 shows the fentanyl acetate (dashed line), acetic acid (solid line) and the neutral form of fentanyl (fentanyl base - dotted line) molar ratio. 当各种比例的芬太尼碱和乙酸在溶液中混合时,这些是在不同pH下存在于溶液中的种类。 When various ratios of fentanyl base and acid are mixed in solution, these species are present in solution at different pH. 预测溶液中乙酸芬太尼(摩尔比I比I)的pH为约6.6。 Prediction of fentanyl acetate solution pH (molar ratio I ratio I) is about 6.6. 在该pH下,约 In this pH, approximately

I %的芬太尼以芬太尼碱存在,对于10mg/mL溶液总芬太尼,所述芬太尼碱将处于或者高于碱的溶解性极限,从而将沉淀出来。 I% of fentanyl in the presence of fentanyl base for a 10mg / mL solution of the total fentanyl, fentanyl base to the solubility limit at or above the base, so as to precipitate out. 通过对制剂补充过量乙酸可以实现增溶,这将导致制剂的酸化并且将因此导致芬太尼碱的量降低。 By excess acetic acid supplement formulation can achieve solubilization, which would lead to acidification of the formulation and resulting in a decrease in the amount of fentanyl base. 然而,在干燥和随后贮存期间,游离乙酸将蒸发,这将不可避免地导致形成水不溶性碱。 However, during drying and subsequent storage, the free acid will evaporate, which will inevitably result in the formation of water-insoluble base. 随后在水中的重构将不允许芬太尼的完全溶解。 Then reconstructed in the water will not allow fentanyl dissolved completely. 使用不挥发性平衡离子将提供芬太尼的固体可溶制剂,只要PH保持在低于芬太尼的pKa至少2pH单位,优选3pH单位即可。 The use of non-volatile counterion soluble solids provide fentanyl formulations, as long as the PH is maintained at least below the pKa of fentanyl 2pH units, preferably the unit can 3pH. 这可以通过向制剂提供至少稍微过量的不挥发性平衡离子(即,不挥发性平衡离子与芬太尼的摩尔比稍微大于I比I)来实现。 This is achieved by providing at least a slight excess of the non-volatile counterion formulations (i.e., molar ratio of the non-volatile counterion I ratio is slightly greater than fentanyl I) is achieved. 此外,可以向该制剂加入挥发性平衡离子而不影响干燥涂层的溶解性。 Furthermore, this formulation may be added without affecting the solubility of the volatile counterion dried coating.

[0270] 图8显示了乙酸(实线)和hPTH(l_34)的中性形式(点线)的摩尔比。 [0270] Figure 8 shows the molar ratio of acetic acid (solid line) and hPTH (l_34) neutral form (dotted line). 预测溶液中hPTH(1-34)六乙酸盐(摩尔比I比6)的pH为约5 (见图5)。 Prediction solution pH hPTH (1-34) hexaacetates (molar ratio I 6) is about 5 (see FIG. 5). 在该pH下,可忽略量的hPTH(l-34)以hPTH(l-34)0净电荷(PTHO-见图6中“O”电荷种类的电荷曲线)存在,并且hPTH(l-34)在20%过量浓度下在水中是高度可溶的。 In this pH, a negligible amount of hPTH (l-34) 0 net charge (see FIG. 6 PTHO- "O" charge curve chargeable species) it is present in an hPTH (l-34), and hPTH (l-34) concentration in excess of 20% are highly soluble in water. 与芬太尼的情况相同,在干燥和随后贮存期间,挥发性游离乙酸将蒸发,其将导致移向更高PH,其导致形成水不溶性PTHO。 As in the case of fentanyl, during drying and subsequent storage, the volatile was evaporated to the free acid, which will result in higher toward PH, which results in the formation of water-insoluble PTHO. 随后在水中重构将不允许hPTH(l-34)的完全溶解。 Followed by reconstitution in water will not allow hPTH (l-34) was completely dissolved. 使用不挥发性平衡离子将提供hPTH(l-34)的固体可溶制剂,只要pH保持在低于hPTH(l-34)的pi至少2.5pH单位,优选3pH单位即可。 The use of non-volatile counterion provides a solid hPTH (l-34) soluble preparation, as long as the pH is maintained at less than pi hPTH (l-34) of at least 2.5pH units, preferably the unit can 3pH. 这可以通过对hPTH(1-34)的每种分子提供至少约2种不挥发性平衡离子来实现。 This is achieved by providing at least about two kinds of non-volatile counterion hPTH (1-34) is achieved in each molecule. 与芬太尼的情况相同,可以向该制剂加入挥发性平衡离子而不影响干燥涂层的溶解性。 As in the case of fentanyl, can be added to the formulation without affecting the solubility of the volatile counterion dried coating.

[0271] 实施例2 [0271] Example 2

[0272] 制备含有hPTH(l_34)的几种水性制剂。 [0272] Several aqueous formulation hPTH (l_34) is prepared containing. 这些制剂含有挥发性平衡离子乙酸。 These preparations contain a volatile counterion acetate. 几种制剂含有额外的不挥发性平衡离子盐酸、羟基乙酸或者酒石酸(见表I)。 Several formulations contain additional non-volatile counterion hydrochloric acid, tartaric acid or glycolic acid (see Table I). 微突出物阵列(微突出物长200 μ m,每个阵列595个微突出物)具有2cm2的皮肤接触区。 Microprojection arrays (microprojection length 200 μ m, each microprojection array 595) having a skin contacting area of ​​2cm2. 使用2002年3月15日提交的美国专利申请序号10/099,604中公开的方法和装置,通过将阵列穿过携带hPTH(l-34)制剂的旋转鼓用这些制剂涂覆微突出物的顶端,将所述专利申请完整引用作为本文的参考。 U.S. Patent Application Serial No. 20,023 filed May 15, 10 in the method and apparatus disclosed 099,604 /, passing through the array by carrying hPTH (l-34) with the rotary drum formulations these formulations was coated microprojection tip, the complete patent application incorporated herein by reference. 在2-8°C下在每个微突出物阵列上进行四次连续涂覆。 Four times continuously coated on each microprojection array at 2-8 ° C. 通过在275nm波长下的紫外光谱评估阵列上涂覆的肽的量。 By the amount of coating on the UV spectrum at 275nm wavelength evaluation array peptides. 扫描电子显微镜术揭示固体涂层具有非常平滑的表面,没有断裂迹象。 Scanning electron microscopy revealed solid coating having a very smooth surface, no signs of fracture. 此外,观察到微突出物到微突出物的涂层的良好均一性,其中涂层局限于微突出物顶部的前100 μ m。 Further, the micro-projections were observed to good uniformity of microprojection coating composition, wherein the coating is restricted to the micro-protrusion 100 μ m before the top thereof. 一些顶端涂覆的阵列随后用于在无毛豚鼠(HGPs)中进行药物递送研究。 Some of the tips of the array is then applied to study drug for delivery in hairless guinea pigs (HGPs).

[0273] 通过肌内注射甲苯噻嗪(8mg/kg)和盐酸氯胺酮(44mg/kg)麻醉HGP。 [0273] by intramuscular injection of xylazine (8mg / kg) and ketamine hydrochloride (44mg / kg) anesthesia HGP. 对麻醉的HGP通过颈动脉插入导管。 HGP anesthetized cannulated through the carotid artery. 将导管用肝素化盐水(20IU/mL)冲洗以防止凝固。 The catheter with heparinized saline (20IU / mL) flushed to prevent clotting. 在整个实验中通过向导管直接注射戊巴比妥钠(32mg/mL)使动物保持在麻醉状态(0.1mL/注射)。 Throughout the experiment the catheter by direct injection of sodium pentobarbital (32mg / mL) Animals were kept under anesthesia (0.1mL / injection). 应用涂覆的微突出物阵列之前,将血样采集到肝素化小瓶(肝素的终浓度为15IU/mL),该血样作为O或者基线样品。 Before the coated microprojection array of applications, heparinized blood samples collected into a vial (final heparin concentration of 15IU / mL), the blood sample as O or baseline sample.

[0274] 用弹簧驱动的冲击敷料器(总能量=0.4焦耳,以小于10毫秒递送)将经涂覆的微突出物阵列应用于麻醉动物的胁腹,所述敷料器的类型公开在2001年10月12日提交的美国专利申请序号09/976,798中,将其完整引用作为本文参考。 [0274] with a spring-driven impact applicator (total energy = 0.4 Joules, delivered in less than 10 msec) is applied to the flank of the anesthetized animal was coated microprojection array type applicator is disclosed in the 2001 US Patent application serial No. 12 October filed 09 / 976,798, which is fully incorporated herein by reference. 所应用的系统包含经涂覆的微突出物阵列装置,将其用粘合剂粘附到LDPE衬垫的中心(7cm2盘)。 Microprojection array system comprises means applied coated, with an adhesive which is adhered to the central pad of LDPE (7cm2 disk). 将贴剂在皮肤上保持I小时(η = 4-5)。 Holding the patch on the skin I h (η = 4-5). 一组动物(η = 5)接受静脉内注射22 μ g hPTH(l_34)而不是微突出物阵列。 One group of animals (η = 5) received an intravenous injection of 22 μ g hPTH (l_34) instead microprojection array. 贴剂应用或者IV注射后以一定时间间隔通过颈动脉导管收集血样。 Patch application or IV injection after a time interval Blood samples were collected via the carotid catheter. 立即离心所有血样以收集血浆,然后将其在_80°C贮存直到分析。 All blood samples were immediately centrifuged to collect plasma, which was then stored until analysis at _80 ° C. 通过EIA测定血浆hPTH(1-34),EIA是来自Peninsula Lab.(San Carlos, CA)的用于hPTH(l_34)的商业化酶免疫测定试齐U盒。 Measured by EIA Plasma hPTH (1-34), EIA from Peninsula Lab. (San Carlos, CA) commercial enzyme immunoassay test box for flush U hPTH (l_34) a. 基于与静脉内施用hPTH(l·-34)相比曲线下面积(AUC)计算来外推通过微突出物阵列递送的hPTH(l-34)剂量。 Based on comparison with intravenous administration of hPTH (l · -34) area under the curve (AUC) is calculated by extrapolating microprojection array delivery hPTH (l-34) dose.

[0275] 结果在表I中显示,其表明从每种固体制剂递送了不同量的hPTH(l_34)。 [0275] The results are shown in Table I, which shows that different amounts of delivered hPTH (l_34) from each of the solid preparation. 仅含有hPTH(l-34)乙酸盐的固体制剂(N0.1和2)平均递送小于2 μ g。 Containing only hPTH (l-34) solid preparation acetate (N0.1 and 2) delivering an average of less than 2 μ g. 加入不挥发性平衡离子羟基乙酸(N0.5)后,向hPTH(l-34)乙酸盐加入不挥发性平衡离子使递送显著增加到最高达 After addition of the non-volatile counterion glycolic acid (N0.5), to hPTH (l-34) acetate was added to make a non-volatile counter ion delivery was significantly increased up to

11.2μ g。 11.2μ g. 试验的两种其他不挥发性平衡离子酒石酸(N0.6)和盐酸(N0.3和4)也增加了hPTH(l-34)递送。 The other two tests nonvolatile counterion tartrate (N0.6) and hydrochloric acid (N0.3 and 4) also increased hPTH (l-34) delivered.

[0276]表1 [0276] TABLE 1

[0277] 无毛豚鼠中PTH制剂和hPTH(l_34)递送 [0277] Hairless guinea pigs PTH formulation and hPTH (l_34) delivery

[0278] [0278]

Figure CN1842320BD00251

[0279] 实施例3 [0279] Example 3

[0280] 为了证明含有挥发性平衡离子的涂层的排除,我们用pH5的水性制剂涂覆Icm2钛盘,所述水性制剂为通过溶解20wt%的肽(一种hGRF类似物)的乙酸盐形式制备的。 [0280] To demonstrate a coating containing volatile negative counterions, we pH5 Icm2 aqueous formulation coated titanium plate, the aqueous formulation is prepared by dissolving 20wt% of the peptide (s hGRF analog) acetate preparation forms. 涂覆后,每个盘在20mL氮气氛下室温下保存3个月。 After coating, each tray for 3 months at room temperature under a nitrogen atmosphere 20mL.

[0281] 表2中的结果比较了最初和3个月时间点时乙酸盐/肽摩尔比。 [0281] Table 2. Comparison of the results of the initial molar ratio of 3-month time points and acetate / peptide. 在一摩尔肽的最初时间点,有6.5摩尔乙酸。 At a first time point molar peptide, 6.5 moles of acetic acid. 在pH5时,肽具有约4.5个正电荷(见图9),剩下每摩尔肽2摩尔游离乙酸。 At pH 5, about 4.5 peptide having positive charges (see FIG. 9), the remaining 2 moles per mole of the free peptide acid. 环境条件贮存3个月后,每摩尔肽的乙酸盐摩尔数降低到3.8,表明挥发性平衡离子从涂层的排除。 After 3 months storage of environmental conditions, the number of moles per mole of the peptide acetate is decreased to 3.8, indicating a volatile counterion excluded from the coating. 从图9的电荷特征外推表明水中涂层的重构将产生pH9.5的溶液,其代表PH从最初溶液的pH的显著增加。 From the outer charge characteristics of Fig. 9 show push reconstitution in water will produce a coating solution pH9.5, PH representing a significant increase from the initial pH of the solution.

[0282] 表2 Ti涂覆的样品中乙酸盐/hGRF类似物摩尔比 [0282] The coated samples in Table 2 Ti acetate / hGRF analogues molar ratio

[0283] [0283]

Figure CN1842320BD00261

[0284] 不背离本发明的精神和范围,技术人员可以对本发明做出多种改变和修饰以使其适于多种用途和条件。 [0284] without departing from the spirit and scope of the invention, the art can make various changes and modifications of the invention to adapt it to various usages and conditions. 同样地,这些改变和修饰适当地、等同地、并且意在处于所附权利要求书的等价方案的完整范围内。 Similarly, such changes and modifications as appropriate, equivalently, and are intended to be within the full scope of the appended claims or the equivalents.

Claims (24)

1.用于涂覆具有穿刺角质层的微突出物的经皮递送装置的组合物,其包含hPTH(l-34)和非挥发性平衡离子的制剂,其中所述hPTH(l-34)在所述制剂pH下具有正电荷,且其中所述非挥发性平衡离子是弱酸或强酸,其中所述非挥发性平衡离子选自:(i)具有至少一个酸性PKa和在Patm下高于50°C的熔点或者高于170°C的沸点的弱酸,(ii)具有至少两个酸性PKa和至少一个碱性pKa的酸性两性离子,从而与碱性基团数目相比具有至少一个额外的酸性基团,(iii)具有至少一个低于2的pKa的强酸,其中所述非挥发性平衡离子以中和在制剂的PH下所述hPTH(l-34)上存在的电荷所必需的量存在,其中hPTH(l-34)有在4到10的pH下不带电种类和带电种类之间至少I比100的摩尔比,且其中所述制剂当干燥时具有增加的PH稳定性和溶解性。 Microprojections composition for coating having 1. stratum corneum-piercing transdermal delivery device, the formulation comprising hPTH (l-34) and non-volatile counterion, wherein the hPTH (l-34) in the pH of the formulation has a positive charge, and wherein the non-volatile counterion is a weak acid or a strong acid, wherein the non-volatile counterion is selected from: (i) at least one having PKa values ​​above and at Patm 50 ° C or a melting point of 170 ° C above the boiling point of a weak acid, (ii) having at least two acidic zwitterionic pKa values ​​and at least one basic pKa, so that compared to the number of basic groups having at least one additional acidic groups group, (iii) at least one strong acid having a pKa 2 below, wherein the non-volatile counterions to neutralize the formulation at PH hPTH (l-34) present on the amount of charge necessary to present, wherein hPTH (l-34) has at least pH 4 to 10. the molar ratio I 100 between the charged species and uncharged species, PH and having increased stability and solubility when said formulation was dried.
2.权利要求1的组合物,其中所述弱酸选自柠檬酸、琥珀酸、羟基乙酸、葡糖酸、葡糖醛酸、乳酸、苹果酸、丙酮酸、酒石酸、羟基丙二酸和富马酸。 2. The composition of claim 1, wherein said weak acid selected from citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid and fumaric acid.
3.权利要求1的组合物,其中所述制剂具有pH,所述生物活性剂在所述制剂pH下具有正电荷,并且所述非挥发性平衡离子是强酸。 The composition of claim 1, wherein the pH of said formulation has, said biologically active agent has a positive charge at the pH of the formulation, and the non-volatile counterion is a strong acid.
4.权利要求3的组合物,其中所述强酸选自盐酸、氢溴酸、硝酸、磺酸、硫酸、马来酸、磷酸、苯磺酸和甲磺酸。 The composition of claim 3, wherein the strong acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid.
5.权利要求1的组合物,其中所述制剂具有pH,所述hPTH(l-34)在所述制剂pH下具有正电荷,并且所述非挥发性平衡离子包含平衡离子的混合物,所述混合物包含至少一种非挥发性强酸和至少一种非挥发性弱酸,其中所述非挥发性强酸平衡离子具有至少一个低于2的pKa,且其中所述非挥发性弱酸平衡离子具有至少一个酸性pKa和在Patm下高于50°C的熔点或者高于170°C的沸点。 The composition of claim 1, wherein the pH of said preparation having the hPTH (l-34) having a positive charge at the pH of the formulation, and the non-volatile counterion comprises a mixture of counterions, the a mixture comprising at least one strong acid and at least one non-volatile non-volatile weak acid, wherein the non-volatile counterion is a strong acid having a pKa below at least 2, and wherein the non-volatile weak acid counterions having at least one acidic pKa and a melting point higher than at 50 ° C at Patm or above the boiling point of 170 ° C.
6.权利要求1的组合物,其中所述制剂具有pH,所述hPTH(l-34)在所述制剂pH下具有正电荷,并且所述非挥发性平衡离子包含平衡离子的混合物,所述混合物包含至少一种非挥发性酸和至少一种挥发性弱酸,其中所述非挥发性酸平衡离子选自: (i)具有至少一个酸性PKa和在Patm下高于50°C的熔点或者高于170°C的沸点的弱酸, (ii)具有至少两个酸性pKa和至少一个碱性pKa的酸性两性离子,从而与碱性基团数目相比具有至少一个额外的酸性基团,和(iii)具有至少一个低于2的pKa的强酸;且其中所述挥发性弱酸具有至少一个高于2的pKa和在Patm下低于50°C的熔点或者低于170°C的沸点。 The composition of claim 1, wherein the pH of said preparation having the hPTH (l-34) having a positive charge at the pH of the formulation, and the non-volatile counterion comprises a mixture of counterions, the a mixture comprising at least one non-volatile acid and at least one volatile weak acid, wherein the non-volatile acid counterion is selected: (i) at least one acidic PKa and having a melting point above 50 ° C or higher at Patm weak acid at the boiling point of 170 ° C, (ii) having at least two acidic pKa and zwitterionic acidic pKa of the at least one basic, as compared with the number of basic groups having at least one additional acidic group, and (iii ) at least a strong acid having a pKa less than 2; and wherein said volatile weak acid having a pKa of at least 2 and having a boiling point higher than at 50 ° C below the melting point at or below 170 ° C Patm is.
7.用于经皮递送生物活性剂的装置,其包含用制剂涂覆的至少一个角质层穿刺性微突出物,其中所述制剂包含hPTH(l-34)和非挥发性平衡离子,其中所述hPTH(l-34)在所述制剂PH下具有正电荷,且其中所述非挥发性平衡离子是弱酸或强酸,其中所述非挥发性平衡离子选自:(i)具有至少一个酸性PKa和在Patm下高于50°C的熔点或者高于170°C的沸点的弱酸,Qi)具有至少两个酸性PKa和至少一个碱性pKa的酸性两性离子,从而与碱性基团数目相比具有至少一个额外的酸性基团,(iii)具有至少一个低于2的pKa的强酸,其中所述非挥发性平衡离子以中和在制剂的PH下所述hPTH (1-34)上存在的电荷所必需的量存在,其中所述hPTH有在4到10的pH下不带电种类和带电种类之间至少I比100的摩尔比,并且所述制剂当干燥时具有增加的PH稳定性和溶解性。 7. A device for the transdermal delivery of the biologically active agent, which comprises using at least one stratum corneum piercing microprojections coated formulation, wherein the formulation comprises hPTH (l-34) and non-volatile counterion, wherein said hPTH (l-34) having a positive charge at the formulation PH, and wherein said non-volatile counterion is a weak acid or a strong acid, wherein the non-volatile counterion is selected from: (i) at least one acid having a PKa and weak acids having a boiling point above the melting point of 50 ° C at Patm or above 170 ° C, and Qi) having at least two pKa values ​​and at least one acidic pKa of the basic zwitterion, as compared with the number of basic groups having at least one additional acidic group, (iii) at least one strong acid having a pKa 2 below, wherein the non-volatile counterions to neutralize the formulation at PH present on hPTH (1-34) the amount of charge required to present, wherein the molar ratio of hPTH have at least pH 4 to 10. the ratio of I 100 between the charged species and uncharged species, and the formulation has an increased stability, and dissolution when PH dried sex.
8.权利要求7的装置,其中所述微突出物适于通过角质层穿刺到小于500微米的深度。 8. The apparatus of claim 7, wherein said microprojection adapted to puncture to a depth less than 500 microns through the stratum corneum.
9.权利要求7的装置,其中所述涂层的厚度等于或者小于所述微突出物的厚度。 9. The apparatus of claim 7, wherein said coating has a thickness equal to or smaller than the thickness of said microprojection thereof.
10.用于涂覆具有角质层穿刺性微突出物的经皮递送装置的组合物,其包含hPTH(l-34)和非挥发性平衡离子和制剂佐剂的制剂,其中所述hPTH(l-34)在所述制剂pH下具有正电荷,且其中所述非挥发性平衡离子是弱酸或强酸,其中所述非挥发性平衡离子选自:(i)具有至少一个酸性PKa和在Patm下高于50°C的熔点或者高于170°C的沸点的弱酸,(ii)具有至少两个酸性PKa和至少一个碱性pKa的酸性两性离子,从而与碱性基团数目相比具有至少一个额外的酸性基团,(iii)具有至少一个低于2的pKa的强酸,其中所述非挥发性平衡离子以中和在制剂的PH下所述hPTH(l-34)上存在的电荷所必需的量存在,其中所述hPTH有在4到10的pH下不带电种类和带电种类之间至少I比100的摩尔比,且其中所述制剂当干燥时具有增加的PH稳定性和溶解性。 10. A composition for coating having a stratum corneum piercing microprojections of a transdermal delivery device, comprising hPTH and non-volatile counterion formulations and formulation adjuvant (l-34), wherein the hPTH (L -34) said formulation having a pH in the positive charge, and wherein the non-volatile counterion is a weak acid or a strong acid, wherein the non-volatile counterion is selected from: (i) having a PKa of at least one acidic and at Patm weak acid at 50 ° C above the melting point or above the boiling point of 170 ° C, (ii) having at least two acidic zwitterionic pKa values ​​and at least one basic pKa, thereby having at least one basic group compared to the number additional acidic group, (iii) at least one strong acid having a pKa 2 below, wherein the non-volatile counterions to neutralize the formulation at PH hPTH (l-34) present on the charge required present in an amount wherein the molar ratio of hPTH have at least pH 4 to 10. the ratio of I 100 between the charged species and uncharged species, PH and having increased stability and solubility when said formulation was dried.
11.权利要求10的组合物,其中所述制剂佐剂包含抗氧化剂。 11. The composition of claim 10, wherein the adjuvant formulation comprises an antioxidant.
12.权利要求10的组合物,其中所述制剂佐剂包含表面活性剂。 12. The composition of claim 10, wherein the adjuvant formulation comprises a surfactant.
13.权利要求10的组合物,其中所述制剂佐剂包含两亲的聚合物。 13. The composition of claim 10, wherein said formulation adjuvant comprises an amphiphilic polymer.
14.权利要求10的组合物,其中所述制剂佐剂包含亲水聚合物。 14. The composition of claim 10, wherein the adjuvant formulation comprises a hydrophilic polymer.
15.权利要求10的组合物,其中所述制剂佐剂包含生物相容的载体。 15. The composition of claim 10, wherein the adjuvant formulation comprises a biocompatible carrier.
16.权利要求10的组合物,其中所述制剂佐剂包含稳定剂。 16. The composition of claim 10, wherein the adjuvant formulation comprises a stabilizer.
17.权利要求10的组合物,其中所述制剂佐剂包含血管收缩剂。 17. The composition as claimed in claim 10, wherein the adjuvant formulation comprises a vasoconstrictor.
18.权利要求10的组合物,其中所述制剂佐剂包含途径开放调节剂。 18. The composition of claim 10, wherein the adjuvant formulation comprises a pathway patency modulator.
19.权利要求10的组合物,其中所述制剂佐剂包含增溶/络合剂。 19. The composition of claim 10, wherein the adjuvant formulation comprises a solubilising / complexing agent.
20.权利要求10的组合物,其中所述制剂佐剂包含非水性溶剂。 20. The composition as claimed in claim 10, wherein the adjuvant formulation comprises a non-aqueous solvent.
21.权利要求10的组合物,其中所述制剂佐剂具有小于500厘泊和大于3厘泊的粘度。 21. The composition as claimed in claim 10, wherein the adjuvant formulation having a viscosity of less than 500 centipoise and greater than 3 centipoise.
22.将生物活性剂涂层应用于经皮递送装置的方法,其中所述经皮递送装置包含许多角质层穿刺性微突出物,所述方法包括步骤: 提供所述生物活性剂的制剂,其中所述活性剂是hPTH ; 通过加入非挥发性平衡离子稳定所述制剂的pH,其中所述非挥发性平衡离子是弱酸或强酸,其中所述非挥发性平衡离子选自:(i)具有至少一个酸性PKa和在Patm下高于50°C的熔点或者高于170°C的沸点的弱酸,(ii)具有至少两个酸性pKa和至少一个碱性pKa的酸性两性离子,从而与碱性基团数目相比具有至少一个额外的酸性基团,(iii)具有至少一个低于2的pKa的强酸,其中所述非挥发性平衡离子以中和在制剂的pH下所述hPTH(1-34)上存在的电荷所必需的量存在,其中所述hPTH有在4到10的pH下不带电种类和带电种类之间至少I比100的摩尔比;和对所述微突出物应用所述制剂。 22. The method of transdermal delivery device is applied to the biologically active agent through the coating, wherein the transdermal delivery device comprises a plurality of stratum corneum piercing microprojections, said method comprising the steps of: providing a formulation of said biologically active agent, wherein the active agent is hPTH; pH by the addition of the non-volatile counterion stable formulation, wherein the non-volatile counterion is a weak acid or a strong acid, wherein the non-volatile counterion is selected from: (i) having at least pKa values ​​and a melting point above 50 ° C at Patm or above the boiling point of 170 ° C weak acid, (ii) having at least two acidic pKa, and at least one acidic pKa basic zwitterion, whereby the basic group having at least one group as compared to the number of additional acidic group, (iii) at least one strong acid having a pKa 2 below, wherein the non-volatile counterions to neutralize the pH of the formulation at the hPTH (1-34 ) present on the amount of charge necessary to present, wherein the hPTH have at least pH 4 to 10. the ratio between I charged species and uncharged species molar ratio of 100; the formulation and application of the microprojections .
23.权利要求22的方法,其中稳定所述制剂的pH的步骤包括加入足够的非挥发性平衡离子以中和所述生物活性剂上的电荷。 23. The method of claim 22, wherein the step of stabilizing said pH of the formulation comprising adding sufficient non-volatile counterions to neutralize the charge of the biologically active agent.
24.权利要求23的方法,其中向所述生物活性剂加入过量平衡离子以便控制pH和提供足够缓冲能力。 24. The method of claim 23, wherein the counterion is added in excess to the biologically active agent in order to control pH and to provide adequate buffering capacity.
CN2004800243347A 2003-06-30 2004-06-29 Formulations for coated microprojections containing non-volatile counterions CN1842320B (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US48402003P true 2003-06-30 2003-06-30
US60/484,020 2003-06-30
PCT/US2004/021004 WO2005004842A2 (en) 2003-06-30 2004-06-29 Formulations for coated microprojections containing non-volatile counterions

Publications (2)

Publication Number Publication Date
CN1842320A CN1842320A (en) 2006-10-04
CN1842320B true CN1842320B (en) 2013-06-19

Family

ID=34062010

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2004800243347A CN1842320B (en) 2003-06-30 2004-06-29 Formulations for coated microprojections containing non-volatile counterions

Country Status (13)

Country Link
US (2) US7579013B2 (en)
EP (1) EP1638523B8 (en)
JP (1) JP5456234B2 (en)
KR (1) KR20060038407A (en)
CN (1) CN1842320B (en)
AR (1) AR044964A1 (en)
AU (1) AU2004255218A1 (en)
BR (1) BRPI0412029A (en)
CA (1) CA2530531A1 (en)
ES (1) ES2437565T3 (en)
MX (1) MXPA06000281A (en)
TW (1) TW200518771A (en)
WO (1) WO2005004842A2 (en)

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6918901B1 (en) * 1997-12-10 2005-07-19 Felix Theeuwes Device and method for enhancing transdermal agent flux
EP1341453B1 (en) * 2000-10-13 2009-04-15 Alza Corporation Apparatus and method for piercing skin with microprotrusions
US7419481B2 (en) * 2000-10-13 2008-09-02 Alza Corporation Apparatus and method for piercing skin with microprotrusions
MXPA03003303A (en) * 2000-10-13 2004-12-13 Johnson & Johnson Microprotrusion member retainer for impact applicator.
RU2282468C2 (en) * 2000-10-26 2006-08-27 Алза Корпорейшн Device having coated micro projections for carrying out transdermal drug delivery
WO2002074173A1 (en) * 2001-03-16 2002-09-26 Alza Corporation Method and apparatus for coating skin piercing microprojections
US20020193729A1 (en) * 2001-04-20 2002-12-19 Cormier Michel J.N. Microprojection array immunization patch and method
DK1638468T3 (en) * 2003-06-30 2007-12-17 Alza Corp Method for coating skin piercing micro projections
US20050123507A1 (en) 2003-06-30 2005-06-09 Mahmoud Ameri Formulations for coated microprojections having controlled solubility
MXPA06000281A (en) * 2003-06-30 2006-07-03 Johnson & Johnson Formulations for coated microprojections containing non-volatile counterions.
JP2007521092A (en) * 2003-07-02 2007-08-02 アルザ・コーポレーシヨン Immune patches and methods for microprojection arrays
CN1863572A (en) * 2003-08-04 2006-11-15 阿尔扎公司 Method and device for enhancing transdermal agent flux
US8524272B2 (en) 2003-08-15 2013-09-03 Mylan Technologies, Inc. Transdermal patch incorporating active agent migration barrier layer
EP1658035A4 (en) 2003-08-25 2007-08-22 3M Innovative Properties Co Delivery of immune response modifier compounds
WO2005042702A2 (en) * 2003-10-23 2005-05-12 Alza Corporation Compositions of stabilized dna for coating microprojections
AU2004285484A1 (en) * 2003-10-24 2005-05-12 Alza Corporation Pretreatment method and system for enhancing transdermal drug delivery
US7455654B2 (en) * 2003-10-28 2008-11-25 Alza Corporation Method and apparatus for reducing the incidence of tobacco use
AU2004287414B2 (en) 2003-10-31 2010-11-25 Alza Corporation Self-actuating applicator for microprojection array
AU2004292954A1 (en) * 2003-11-13 2005-06-09 Alza Corporation Composition and apparatus for transdermal delivery
US20050271684A1 (en) * 2004-04-13 2005-12-08 Trautman Joseph C Apparatus and method for transdermal delivery of multiple vaccines
ES2568259T3 (en) * 2004-05-13 2016-04-28 Alza Corporation Apparatus and method for transdermal administration of parathyroid hormone agents
CN101232874A (en) * 2004-08-11 2008-07-30 阿尔扎公司 Apparatus and method for transdermal delivery of natriuretic peptides
WO2007061781A1 (en) * 2005-11-18 2007-05-31 3M Innovative Properties Company Coatable compositions, coatings derived therefrom and microarrays having such coatings
CA2593112A1 (en) * 2005-01-21 2006-07-27 Alza Corporation Therapeutic peptide formulations for coating microneedles with improved stability containing at least one counterion
US7488316B2 (en) * 2005-01-25 2009-02-10 Microchips, Inc. Control of drug release by transient modification of local microenvironments
AU2006214236A1 (en) * 2005-02-16 2006-08-24 Alza Corporation Apparatus and method for transdermal delivery of erythropoetin-based agents
CA2610626A1 (en) * 2005-06-02 2006-12-07 Alza Corporation Method for terminal sterilization of transdermal delivery devices
JP5438872B2 (en) * 2005-06-02 2014-03-12 アルザ コーポレイション Final sterilization method for transdermal delivery devices
CA2619452A1 (en) * 2005-09-12 2007-03-22 Alza Corporation Coatable transdermal delivery microprojection assembly
US8554317B2 (en) * 2005-11-30 2013-10-08 3M Innovative Properties Company Microneedle arrays and methods of use thereof
AU2006336187A1 (en) * 2005-12-28 2007-07-26 Alza Corporation Stable therapeutic formulations
CA2680690A1 (en) * 2006-03-15 2007-09-20 Alza Corporation Apparatus and method for transdermal delivery of parathyroid hormone agents to prevent or treat osteopenia
US20070293816A1 (en) * 2006-04-25 2007-12-20 Alza Corporation Microprojection Array Application with Grouped Microprojections for High Drug Loading
US20070299388A1 (en) * 2006-04-25 2007-12-27 Alza Corporation Microprojection array application with multilayered microprojection member for high drug loading
US7771542B1 (en) 2006-05-30 2010-08-10 Stone Chemical Company Compositions and methods for removing lead from metal surfaces
KR101430627B1 (en) 2008-05-13 2014-08-14 유니버시티 오브 캔사스 Metal Abstraction Peptide(MAP) Tag and Associated Methods
ME02474B (en) 2010-05-12 2017-02-20 Radius Health Inc Therapeutic regimens
AU2011258288B2 (en) 2010-05-28 2015-02-12 3M Innovative Properties Company Aqueous formulations for coating microneedle arrays
BR112013007685A2 (en) 2010-09-28 2016-08-09 Radius Health Inc applications related to selective amphrogen receptor modulators
WO2012071559A2 (en) * 2010-11-23 2012-05-31 Presage Biosciences, Inc. Therapeutic methods and compositions for solid delivery
CN102090904B (en) * 2011-02-17 2013-04-03 中国中医科学院中医临床基础医学研究所 Rapid allergic skin test detector of Chinese medicine injection
US20120222979A1 (en) 2011-03-04 2012-09-06 Elwha LLC, a limited liability company of the State of Delaware Glassy compositions
NL2007382C2 (en) * 2011-09-09 2013-03-12 Univ Leiden Method to coat an active agent to a surface.
US9675675B2 (en) 2011-11-30 2017-06-13 3M Innovative Properties Company Microneedle device having a peptide therapeutic agent and an amino acid, methods of making and using the same
WO2013181461A2 (en) 2012-06-01 2013-12-05 University Of Kansas Metal abstraction peptide with superoxide dismutase activity
WO2014126104A1 (en) 2013-02-13 2014-08-21 久光製薬株式会社 Microneedle-coating composition and microneedle device
CA2900920C (en) 2013-02-13 2018-08-21 Hisamitsu Pharmaceutical Co., Inc. Microneedle coating composition and microneedle device
US9782344B2 (en) * 2013-08-22 2017-10-10 Zp Opco, Inc. Stable glucagon peptide formulations
EP3035952B1 (en) * 2013-08-22 2018-12-26 ZP Opco, Inc. Stable glucagon peptide formulations
KR20170105105A (en) 2015-01-27 2017-09-18 쓰리엠 이노베이티브 프로퍼티즈 컴파니 Alum-containing coating formulation for micro needle vaccine patch
US9375478B1 (en) 2015-01-30 2016-06-28 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9925233B2 (en) 2015-01-30 2018-03-27 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9687526B2 (en) 2015-01-30 2017-06-27 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9937223B2 (en) 2015-01-30 2018-04-10 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9744209B2 (en) 2015-01-30 2017-08-29 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9750785B2 (en) 2015-01-30 2017-09-05 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
CN108135837A (en) * 2015-10-09 2018-06-08 3M创新有限公司 For being coated with the Zn composition of microneedle array
WO2017143345A1 (en) 2016-02-19 2017-08-24 Zp Opco, Inc. Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
CA3047411A1 (en) 2017-01-05 2018-07-12 Radius Pharmaceuticals, Inc. Polymorphic forms of rad1901-2hcl
CN108721598A (en) * 2018-07-03 2018-11-02 宋雪萍 The preparation method and its pharmaceutical composition and preparation of a kind of oxytocin raw material

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001041863A1 (en) 1999-12-10 2001-06-14 Alza Corporation Device and method for enhancing microprotrusion skin piercing

Family Cites Families (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3123212A (en) 1964-03-03 Multiple disposable intracutaneous injector package
USRE25637E (en) 1964-09-08 Means for vaccinating
GB179994A (en) 1921-02-02 1922-05-02 Achilee Macchioni Throttling of the exhaust in a two-stroke cycle internal combustion motor applied to a locomotive for the purpose of increasing the power of the said motor
US2619962A (en) 1948-02-19 1952-12-02 Res Foundation Vaccination appliance
US2893392A (en) 1958-01-08 1959-07-07 American Cyanamid Co Article of manufacture for intracutaneous injections
US3072122A (en) 1959-01-15 1963-01-08 Rosenthal Sol Roy Package for transcutaneous injection
US3136314A (en) 1960-08-01 1964-06-09 Kravitz Harvey Vaccinating devices
US3221739A (en) 1962-03-26 1965-12-07 Rosenthal Sol Roy Injection device
US3221740A (en) 1962-08-31 1965-12-07 Rosenthal Sol Roy Injection device
US3964482A (en) 1971-05-17 1976-06-22 Alza Corporation Drug delivery device
US3678150A (en) 1971-07-27 1972-07-18 American Cyanamid Co Process for improving the stability of ppd, qt and histoplasmin on tine applicators
BE795384A (en) 1972-02-14 1973-08-13 Ici Ltd dressings
OA5448A (en) 1975-10-16 1981-03-31 Manufrance Manufacture Francai Multipenetrating vaccinating device
FR2474856B1 (en) 1980-01-31 1983-10-07 Merieux Inst
SE8501990D0 (en) 1985-04-24 1985-04-24 Pharmacia Ab Beleggningsforfarande
KR970008118B1 (en) 1987-07-09 1997-05-21 호프만, 마쓰 Transdermal therapeutic system
US5051132A (en) * 1989-06-15 1991-09-24 Nippon Kayaku Kabushiki Kaisha Lyophilized preparation of 6-(3-dimethylaminopropionyl)forskolin
CA2016900A1 (en) 1989-07-06 1991-01-06 Ronald J. Filipski Tines structure in clinical applicator
EP0429842B1 (en) 1989-10-27 1996-08-28 Korea Research Institute Of Chemical Technology Device for the transdermal administration of protein or peptide drug
JPH04134033A (en) * 1990-01-19 1992-05-07 Nippon Kayaku Co Ltd Lyophilized preparation of ethoposide-2-dimethylamino compound
US5279544A (en) 1990-12-13 1994-01-18 Sil Medics Ltd. Transdermal or interdermal drug delivery devices
DE4242919A1 (en) * 1992-12-18 1994-06-23 Boehringer Mannheim Gmbh A process for the preparation of storage stable aqueous pharmaceutical preparations of G-CSF
DE4341444C2 (en) 1993-12-04 1996-03-14 Lohmann Therapie Syst Lts Active substance-containing plaster, and process for its preparation
US5496801A (en) * 1993-12-23 1996-03-05 Allelix Biopharmaceuticals Inc. Parathyroid hormone formulation
US5487726A (en) 1994-06-16 1996-01-30 Ryder International Corporation Vaccine applicator system
NZ290896A (en) 1994-08-04 1997-04-24 Quadrant Holdings Cambridge Solid dose delivery composition containing a glassy vehicle and at least one guest substance
CA2201315A1 (en) 1994-09-30 1996-04-11 Peter Ping Ling Direct introduction of foreign materials into cells
US6290991B1 (en) 1994-12-02 2001-09-18 Quandrant Holdings Cambridge Limited Solid dose delivery vehicle and methods of making same
EP0796128B1 (en) 1994-12-09 1999-03-10 Novartis AG Transdermal system
US5866536A (en) * 1995-03-31 1999-02-02 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
WO1996037155A1 (en) 1995-05-22 1996-11-28 Silicon Microdevices, Inc. Micromechanical device and method for enhancing delivery of compounds through the skin
AU5869796A (en) 1995-05-22 1996-12-11 Ned A. Godshall Micromechanical patch for enhancing the delivery of compound s through the skin
DE19525607A1 (en) 1995-07-14 1997-01-16 Boehringer Ingelheim Kg Transcorneal drug release system
AT234129T (en) 1996-06-18 2003-03-15 Alza Corp Apparatus for improving transdermal administration of medicaments or the acceptance of body fluids
WO1998000193A1 (en) 1996-07-03 1998-01-08 Altea Technologies, Inc. Multiple mechanical microporation of skin or mucosa
US5741554A (en) 1996-07-26 1998-04-21 Bio Dot, Inc. Method of dispensing a liquid reagent
US5743960A (en) 1996-07-26 1998-04-28 Bio-Dot, Inc. Precision metered solenoid valve dispenser
US5738728A (en) 1996-07-26 1998-04-14 Bio Dot, Inc. Precision metered aerosol dispensing apparatus
WO1998011937A1 (en) 1996-09-17 1998-03-26 Deka Products Limited Partnership System for delivery of drugs by transport
DK0957972T3 (en) 1996-12-20 2003-07-21 Alza Corp A device and method for increasing the transdermal average flux
DE19654391A1 (en) 1996-12-27 1998-07-02 Basf Ag Catalyst for the selective production of propylene from propane
WO1998029298A1 (en) 1996-12-31 1998-07-09 Shell Internationale Research Maatschappij B.V. Spar platform with vertical slots
US5916524A (en) 1997-07-23 1999-06-29 Bio-Dot, Inc. Dispensing apparatus having improved dynamic range
US6918901B1 (en) 1997-12-10 2005-07-19 Felix Theeuwes Device and method for enhancing transdermal agent flux
KR100572539B1 (en) 1997-12-11 2006-04-24 알자 코포레이션 Device for enhancing transdermal agent flux
JP2001525232A (en) 1997-12-11 2001-12-11 アルザ・コーポレーション Apparatus for enhancing the flow of transdermal substance
AT406935T (en) 1997-12-11 2008-09-15 Alza Corp Device for improving the transdermal river of medicaments
ES2180274T3 (en) * 1998-01-30 2003-02-01 Novartis Consumer Health Sa Nasal solutions.
US6091975A (en) 1998-04-01 2000-07-18 Alza Corporation Minimally invasive detecting device
EP1086214B1 (en) 1998-06-10 2009-11-25 Georgia Tech Research Corporation Microneedle devices and methods of their manufacture
JP2002523195A (en) 1998-08-31 2002-07-30 ジョンソン・アンド・ジョンソン・コンシューマー・カンパニーズ・インコーポレイテッド Electron transport device comprising a blade
JP3722268B2 (en) 1998-09-03 2005-11-30 栗田工業株式会社 Antibacterial composition
SE9803517D0 (en) * 1998-10-15 1998-10-15 Astra Ab Pharmaceutical preparation
AR022119A1 (en) * 1998-12-22 2002-09-04 Bausch & Lomb Pheniramine containing compositions and method for the treatment of allergic responses
GB9901253D0 (en) * 1999-01-20 1999-03-10 Isis Innovation Bis-terpyridine-platinum(II) complexes
US6884427B1 (en) 1999-02-08 2005-04-26 Aderans Research Institute, Inc. Filamentary means for introducing agents into tissue of a living host
US6379324B1 (en) 1999-06-09 2002-04-30 The Procter & Gamble Company Intracutaneous microneedle array apparatus
US6256533B1 (en) 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
GB9916316D0 (en) * 1999-07-12 1999-09-15 Quadrant Holdings Cambridge Dry powder compositions
US6623457B1 (en) 1999-09-22 2003-09-23 Becton, Dickinson And Company Method and apparatus for the transdermal administration of a substance
US6835184B1 (en) 1999-09-24 2004-12-28 Becton, Dickinson And Company Method and device for abrading skin
US20020095134A1 (en) 1999-10-14 2002-07-18 Pettis Ronald J. Method for altering drug pharmacokinetics based on medical delivery platform
US20050008683A1 (en) 2000-06-29 2005-01-13 Becton Dickinson And Company Method for delivering interferons to the intradermal compartment
US6743211B1 (en) 1999-11-23 2004-06-01 Georgia Tech Research Corporation Devices and methods for enhanced microneedle penetration of biological barriers
CH694730A5 (en) * 2000-02-09 2005-06-30 Sumitomo Chemical Co A process for producing optically active hemiester.
AU5875501A (en) 2000-05-17 2001-11-26 Senju Pharma Co Ophthalmic solution
US20020061838A1 (en) * 2000-05-17 2002-05-23 Barton Holmquist Peptide pharmaceutical formulations
US6537242B1 (en) 2000-06-06 2003-03-25 Becton, Dickinson And Company Method and apparatus for enhancing penetration of a member for the intradermal sampling or administration of a substance
GB0016002D0 (en) * 2000-06-29 2000-08-23 Glaxo Group Ltd Novel process for preparing crystalline particles
US6589202B1 (en) 2000-06-29 2003-07-08 Becton Dickinson And Company Method and apparatus for transdermally sampling or administering a substance to a patient
US6565532B1 (en) 2000-07-12 2003-05-20 The Procter & Gamble Company Microneedle apparatus used for marking skin and for dispensing semi-permanent subcutaneous makeup
US6440096B1 (en) 2000-07-14 2002-08-27 Becton, Dickinson And Co. Microdevice and method of manufacturing a microdevice
GB0017999D0 (en) * 2000-07-21 2000-09-13 Smithkline Beecham Biolog Novel device
RU2272618C2 (en) * 2000-09-08 2006-03-27 Алза Корпорейшн Method for inhibiting reduction of transdermal drug movement by inhibiting paths closing
AU9682701A (en) 2000-10-13 2002-04-22 Alza Corp Microblade array impact applicator
EP1341453B1 (en) 2000-10-13 2009-04-15 Alza Corporation Apparatus and method for piercing skin with microprotrusions
MXPA03003303A (en) 2000-10-13 2004-12-13 Johnson & Johnson Microprotrusion member retainer for impact applicator.
RU2282468C2 (en) 2000-10-26 2006-08-27 Алза Корпорейшн Device having coated micro projections for carrying out transdermal drug delivery
WO2002064193A2 (en) 2000-12-14 2002-08-22 Georgia Tech Research Corporation Microneedle devices and production thereof
WO2002074173A1 (en) 2001-03-16 2002-09-26 Alza Corporation Method and apparatus for coating skin piercing microprojections
US20020193729A1 (en) 2001-04-20 2002-12-19 Cormier Michel J.N. Microprojection array immunization patch and method
US7963935B2 (en) 2001-04-20 2011-06-21 Alza Corporation Microprojection array having a beneficial agent containing coating
US6881203B2 (en) 2001-09-05 2005-04-19 3M Innovative Properties Company Microneedle arrays and methods of manufacturing the same
CA2500453A1 (en) 2001-09-28 2003-04-03 Biovalve Technologies, Inc. Microneedle with membrane
US6689100B2 (en) 2001-10-05 2004-02-10 Becton, Dickinson And Company Microdevice and method of delivering or withdrawing a substance through the skin of an animal
US20030093040A1 (en) * 2001-10-29 2003-05-15 Mikszta John A. Method and device for the delivery of a substance
EP1485317A2 (en) 2001-11-30 2004-12-15 Alza Corporation Methods and apparatuses for forming microprojection arrays
HU0402605A2 (en) 2001-12-20 2005-06-28 Alza Corporation Device microscopic incisions dropping animal skin tissue
US7015262B2 (en) 2002-05-01 2006-03-21 Lifescan, Inc. Hydrophilic coatings for medical implements
EP1517722B1 (en) 2002-06-28 2006-08-16 Alza Corporation Method of coating transdermal drug delivery devices having coated microprotrusions
AR042815A1 (en) * 2002-12-26 2005-07-06 Alza Corp Delivery device of active agent compounds having members
DK1638468T3 (en) * 2003-06-30 2007-12-17 Alza Corp Method for coating skin piercing micro projections
US20050123507A1 (en) 2003-06-30 2005-06-09 Mahmoud Ameri Formulations for coated microprojections having controlled solubility
MXPA06000281A (en) * 2003-06-30 2006-07-03 Johnson & Johnson Formulations for coated microprojections containing non-volatile counterions.
JP2007521092A (en) * 2003-07-02 2007-08-02 アルザ・コーポレーシヨン Immune patches and methods for microprojection arrays
AU2004287414B2 (en) 2003-10-31 2010-11-25 Alza Corporation Self-actuating applicator for microprojection array
AU2004292954A1 (en) 2003-11-13 2005-06-09 Alza Corporation Composition and apparatus for transdermal delivery
CA2593112A1 (en) * 2005-01-21 2006-07-27 Alza Corporation Therapeutic peptide formulations for coating microneedles with improved stability containing at least one counterion
US9960402B2 (en) 2016-09-07 2018-05-01 Thunder Power New Energy Vehicle Development Company Limited Process of manufacturing a battery system assembly using the battery system assembly press

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001041863A1 (en) 1999-12-10 2001-06-14 Alza Corporation Device and method for enhancing microprotrusion skin piercing

Also Published As

Publication number Publication date
EP1638523A2 (en) 2006-03-29
TW200518771A (en) 2005-06-16
WO2005004842A3 (en) 2005-04-21
JP2007527392A (en) 2007-09-27
US20100221305A1 (en) 2010-09-02
US20040265354A1 (en) 2004-12-30
CN1842320A (en) 2006-10-04
MXPA06000281A (en) 2006-07-03
EP1638523B1 (en) 2013-10-30
EP1638523B8 (en) 2013-12-25
KR20060038407A (en) 2006-05-03
WO2005004842A2 (en) 2005-01-20
AU2004255218A1 (en) 2005-01-20
BRPI0412029A (en) 2006-09-05
ES2437565T3 (en) 2014-01-13
US7579013B2 (en) 2009-08-25
JP5456234B2 (en) 2014-03-26
AR044964A1 (en) 2005-10-12
US8920817B2 (en) 2014-12-30
CA2530531A1 (en) 2005-01-20

Similar Documents

Publication Publication Date Title
US7316665B2 (en) Method and device for the delivery of a substance including a covering
US7846488B2 (en) Masking method for coating a microneedle array
CN100464800C (en) A transdermal drug delivery device with coated microprotrusions
EP1439870B1 (en) Device for the delivery of a substance
CN100571643C (en) Self-actuating applicator for microprojection array
CA2444551C (en) Microprojection array immunization patch and method
US20060036209A1 (en) System and method for transdermal delivery
KR100764699B1 (en) Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure
US20040138610A1 (en) Active agent delivery device having composite members
US20050123565A1 (en) System and method for transdermal vaccine delivery
US9498524B2 (en) Method of vaccine delivery via microneedle arrays
US20040096455A1 (en) Transdermal vaccine delivery device having coated microprotrusions
ES2333849T3 (en) Provision of microsalients presented by a covering containing a beneficial agent.
EP1744683B1 (en) Apparatus and method for transdermal delivery of parathyroid hormone agents
CN100548228C (en) Composition and apparatus for transdermal delivery
CA2451816A1 (en) Intradermal delivery of vaccines and gene therapeutic agents via microcannula
RU2282468C2 (en) Device having coated micro projections for carrying out transdermal drug delivery
CA2629193A1 (en) Coatable compositions, coatings derived therefrom and microarrays having such coatings
CN101151061B (en) Coated microprojections having reduced variability and method for producing same
JP2007510445A (en) Pretreatment methods and systems for promoting transdermal drug delivery
CN102215902A (en) Hollow microneedle array and method
CN102264429B (en) Microneedle device
US20050220854A1 (en) Apparatus and method for transdermal delivery of influenza vaccine
WO2012122162A1 (en) Microneedle devices and methods
US20050106227A1 (en) Delivery of polymer conjugates of therapeutic peptides and proteins via coated microprojections

Legal Events

Date Code Title Description
C06 Publication
C10 Entry into substantive examination
C14 Grant of patent or utility model
CF01